Active Antiretroviral Therapy Initiation Research Articles

Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood.Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2–3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT).Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10−7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis.Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

Higher cardiovascular disease risks in people living with HIV: A systematic review and meta-analysis.

The prognosis of AIDS after active antiretroviral therapy (ART) and the quality of life of people living with HIV (PLWH) are both affected by non-AIDS-related diseases such as cardiovascular disease (CVD). However, the specific risk ratios between PLWH and individuals negative for HIV are poorly understood. We aimed to systematically review and investigate the CVD risk factors associated with HIV. We searched PubMed, Embase, Web of Science, and Cochrane Library databases between 1 January 2015, and 12 May 2023 for articles reported the prevalence and risk factors of CVD such as hypertension, dyslipidaemia, coronary artery disease (CAD), and myocardial infarction (MI). Due to the high heterogeneity, we used a random-effects model to analyse the data. All statistical analyses were performed using Stata/MP 17.0 with 95% confidence intervals (CIs). We analysed 31 eligible studies including 312 913 PLWH. People living with HIV had higher risks of dyslipidaemia (hazard ratio (HR) = 1.53; 95% CI = 1.29, 1.82), CAD (HR = 1.37; 95% CI = 1.24, 1.51), and MI (HR = 1.47; 95% CI = 1.28, 1.68) compared to individuals without HIV. However, there were no significant differences in the prevalence of hypertension between groups (HR = 1.17; 95% CI = 0.97, 1.41). Subgroup analysis revealed that men with HIV, PLWH who smoked and the elderly PLWH had a high prevalence of CVD. Moreover, the disease prevalence patterns varied among regions. In the USA and Europe, for instance, some HRs for CVD were higher than in other regions. Active ART initiation after 2015 appears to have a lower risk of CVD (hypertension, hyperlipidaemia, CAD). All outcomes under analysis showed significant heterogeneity (I2>70%, P < 0.001), which the available study-level variables could only partially account for. People living with HIV had a higher CVD risk than the general population; thus, CVD prevention in PLWH requires further attention. Rapid initiation of ART may reduce the incidence of CVD in PLWH. For timely screening of CVD high-risk individuals and thorough disease management to prevent CVD, further studies are required to evaluate the risk factors for CVD among PLWH, such as age, region, etc. PROSPERO (CRD42021255508).

Independent Effects of HIV and Antiretroviral Therapy on the Oral Microbiome Identified by Multivariate Analyses.

The oral microbiome is an important predictor of health and disease. We recently reported significant yet modest effects of HIV under highly active antiretroviral therapy (ART) on the oral microbiome (bacterial and fungal) in a large cohort of HIV-positive (HIV+) and matched HIV-negative (HIV-) individuals. As it was unclear whether ART added to or masked further effects of HIV on the oral microbiome, the present study aimed to analyze the effects of HIV and ART independently, which also included HIV- subjects on preexposure prophylaxis (PrEP) therapy. Cross-sectional analyses of the effect of HIV devoid of ART (HIV+ ART- versus matched HIV- subjects) showed a significant effect on both the bacteriome and mycobiome (P < 0.024) after controlling for other clinical variables (permutational multivariate analysis of variance [PERMANOVA] of Bray-Curtis dissimilarity). Cross-sectional analyses evaluating the effects of ART (HIV+ ART+ versus HIV+ ART- subjects) revealed a significant effect on the mycobiome (P < 0.007) but not the bacteriome. In parallel longitudinal analyses, ART (before versus after the initiation of ART) had a significant effect on the bacteriome, but not the mycobiome, of HIV+ and HIV- PrEP subjects (P < 0.005 and P < 0.016, respectively). These analyses also revealed significant differences in the oral microbiome and several clinical variables between HIV- PrEP subjects (pre-PrEP) and the HIV-matched HIV- group (P < 0.001). At the species level, a small number of differences in both bacterial and fungal taxa were identified within the effects of HIV and/or ART. We conclude that the effects of HIV and ART on the oral microbiome are similar to those of the clinical variables but collectively are modest overall. IMPORTANCE The oral microbiome can be an important predictor of health and disease. For persons living with HIV (PLWH), HIV and highly active antiretroviral therapy (ART) may have a significant influence on their oral microbiome. We previously reported a significant effect of HIV with ART on both the bacteriome and mycobiome. It was unclear whether ART added to or masked further effects of HIV on the oral microbiome. Hence, it was important to evaluate the effects of HIV and ART independently. For this, multivariate cross-sectional and longitudinal oral microbiome analyses (bacteriome and mycobiome) were conducted within the cohort, including HIV+ ART+ subjects and HIV+ and HIV- (preexposure prophylaxis [PrEP]) subjects before and after the initiation of ART. While we report independent significant effects of HIV and ART on the oral microbiome, we conclude that their influence is similar to that of the clinical variables but collectively modest overall.

Prevalence of anemia among HIV-infected individuals and the associated factors: A single-center, retrospective review of 513 cases

Background: Although a major public health problem around the world, the prevalence of anemia and the associated factors in HIV-infected individuals remains understudied in the Indian context. Objectives: The objective was to assess the prevalence of anemia and the associated factors among HIV-infected individuals. Methods: The records of 513 HIV-affected individuals (M: F: 244:269) aged 12 to 84 years (mean ± SD: 37.5 ± 12.1) were reviewed retrospectively for the presence of anemia and the associated factors. The anemia was defined and severity was graded per the WHO guidelines. Results: Anemia of variable severity was present in 77.7% of the individuals. The female sex(OR: 2.09; Cl: 95%; CI: 1.41–3.10; p &lt; 0.05), CD4+ count ≤ 200 cells/microliter (OR: 2.36; Cl: 95%; CI: 1.59–3.52; p &lt; 0.0001), WBC count &lt; 4000 cells/mm3 (OR: 3.29; Cl: 95%; CI: 0.97–11.14; p &lt; 0.04), platelet count &lt; 100,000 cells/dL (OR: 0.50; Cl: 95%; CI: 0.31–0.81; p &lt; 0.05), before ART (OR: 3.78; Cl: 95%; CI: 2.91–4.91; p &lt; 0.0001), and tuberculosis treatment (OR: 5.88; Cl: 95%; CI: 1.38–25.04; p &lt; 0.05) were factors significantly associated with anemia. The mean duration of highly active antiretroviral therapy (ART) was 3.15 years, with 395 (77%) individuals being on treatment for ≤ five years. ART significantly improved hemoglobin levels (p &lt; 0.0001). Conclusion: Anemia of variable severity remains a significant co-morbidity among HIV-infected individuals, especially females, prior to the initiation of ART, and those with a low CD4+ count or thrombocytopenia and on anti-tuberculosis treatment. The fact that this was a single-center study, its small number of subjects, the retrospective design, and no information on red blood cell indices and the viral load were its important limitations. Key words: AIDS; anemia; ART; CD4+ count; HAART; HIV; India

Hematological parameters abnormalities and associated factors in HIV-positive adults before and after highly active antiretroviral treatment in Goba Referral Hospital, southeast Ethiopia: A cross-sectional study.

Objectives:Hematological abnormalities of the major blood cell lines are frequently reported in patients with HIV-1 infection, in patients without antiretroviral therapy, and during the advanced stages of the disease. Chronic immune activation and inflammation results in the progressive depletion of CD4+ T-cells play a significant role in the clinical progression and pathogenesis of this infection. This study was aimed at assessing the prevalence of hematological abnormalities and their associated factors before and after the initiation of antiretroviral therapy in adults with HIV-1 infection in a referral hospital.Methods:The study was conducted from 1 April to 30 June 2018, at Goba Referral Hospital. A total of 308 HIV-positive adults on treatment were enrolled during the study period. Socio-demographic and clinical data were collected using a structured questionnaire, with pre-highly active antiretroviral therapy data were extracted from medical records while post-treatment immuno-hematological measurements were done on blood samples collected at the time of enrollment.Results:The prevalence of anemia, leukopenia, and thrombocytopenia before initiation of antiretroviral treatment was higher, although anemia and thrombocytopenia decreased correspondingly after initiation of treatment leukopenia increased by 4%. Mean values of immuno-hematological parameters before and after treatment initiation were significant (p < 0.05). CD4+ T-cell count <200 cells/µL was the only independent risk factor for anemia and leukopenia before highly active antiretroviral therapy, while stage IV disease, female sex, zidovudine, lamivudine, and nevirapine treatment, and intestinal parasite infection were predictors of anemia after treatment initiation.Conclusion:The study revealed that hematological abnormalities are common in HIV infection, while the occurrence of abnormalities after highly active antiretroviral therapy initiation. Different risk factors are associated with hematological abnormalities at pre- and post-highly active antiretroviral therapy with regular monitoring of risk factors, adherence to the early initiation of highly active antiretroviral therapy, and conduct of further longitudinal studies are recommended.

Development and Validation of a Prognostic Model for Long-Term Survival after Starting Antiretroviral Therapy: A 15-Year Retrospective Cohort Study in Southwest China

Background: Due to no early assessment tool for HIV individual treatment in rural western China, we aimed to formulate and validate a simple-to-use model to predict long-term overall survival at the initiation of high active antiretroviral therapy (HAART). Methods: In total, 36268 eligible participants on HAART between 2003 and 2018 from Guangxi autonomous region were enrolled and randomized into development and validation cohorts. Optimal predictors were determined based on Cox hazard models and specialists’ advice. A nomogram was drawn for model visualization. Discrimination, calibration, and Clinical utility was measured, respectively. Findings: The prognostic model combined 14 weighted variables including demographic, epidemic, clinical, and laboratory parameters. Age, aspartate transaminase, and serum creatinine were assigned higher risk scores than that of CD4+ T lymphocytopenia count and having opportunistic infections or AIDS-related symptoms. At 3 time points (1-, 3-, and 5-year), the area under the receiver operating characteristic curve ranged from 0·75 to 0·81 and the Brier scores ranged from 0·033 to 0·067. The calibration curves and the DCA curves showed good robustness and acceptable clinical net benefit. The model performances at 1-year and 3-year were better than that at 5-year. Interpretation: The prognostic model incorporating routine baseline data can provide a useful tool for early risk appraisal and treatment management in HAART in rural western China. Moreover, our study underscores the potential risk of non-AIDS-defining events in long-term survival during HAART. Funding Statement: This study was supported by the Guangxi Bagui Honor Scholar grant. Declaration of Interests: All authors have no competing interests to report. Ethics Approval Statement: This study was approved by the Ethics Review Board of Guangxi Center for Disease Control and Prevention (Certificate No.: GXIRB2016-0047-1). We signed a confidentiality agreement and were authorized to use the database for this study.

Immunologic Restoration of People Living with Human Immunodeficiency Virus on Highly Active Anti-retroviral Therapy in Ethiopia: The Focus of Chronic Non-Communicable Disease Co-Morbidities

Background: The life expectancy of people living with Human Immunodeficiency Virus (HIV) has dramatically improved with the much-increased access to antiretroviral therapy. Consequently, a larger number of people living with HIV are living longer and facing the increased burden of non-communicable diseases. This study assessed the effect of chronic non-communicable disease(s) and co-morbidities on the immunologic restoration of HIV infected patients on highly active antiretroviral therapy. Methods: A nested case-control study was conducted among people living with HIV at Jimma University Medical Center from February 20 to August 20, 2016. Cases were HIV infected patients living with chronic non-communicable diseases and controls were people living with HIV only. Patient-specific data were collected using a structured data collection tool to identify relevant information. Data were analyzed using the Statistical Package for Social Science version 20.0. Logistic regressions were used to identify factors associated with outcome. Statistical significance was considered at p-value &lt;0.05. A patient's written informed consent was obtained after explaining the purpose of the study. Results: A total of 240 participants (120 cases and 120 controls) were included in the analysis. Prevalence of hypertension was 12.50%, and diabetes was 10.84%. About 10.42% of study participants were living with multi-morbidity. At baseline, the mean (±SD) age of cases was 42.32±10.69 years, whereas it was 38.41±8.23 years among controls. The median baseline CD4+ cell count was 184.50 cells/µL (IQR: 98.50 - 284.00 cells/µL) for cases and 177.0 cells/µL (IQR: 103.75 - 257.25 cells/µL) for controls. Post-6-months of highly active antiretroviral therapy initiation, about 29.17% of cases and 16.67% of controls had poor immunologic restoration. An average increase of CD4+ cell count was 6.4cells/µL per month among cases and 7.6 cells/µL per month among controls. Male sex [AOR, 3.51; 95% CI, 1.496 to 8.24; p=0.004], smoking history [AOR, 2.81; 95% CI, 1.072, to 7.342; p=0.036] and co-morbidity with chronic non-communicable disease(s) [AOR, 3.99; 95% CI, 1.604 to 9.916; p=0.003)] were independent predictors of poor immunologic restoration. Conclusions: Chronic non-communicable disease(s) have negative effects on the kinetics of CD4+ cell count among HIV-infected patients who initiated antiretroviral therapy. So the integration of chronic non-communicable disease-HIV collaborative activities will strengthen battle to control the double burden of chronic illnesses.

Immune Reconstitution Syndrome with Initiation of Treatment of HBV/HIV Co-infection: Activity Flare associated with E antigen Seroconversion

Immune reconstitution syndrome is a recognized complication with initiation of highly active antiretroviral therapy for acquired immune deficiency syndrome patients co-infected with hepatitis B. Hepatitis B flares are seen in 20%-25% of patients after initiation of highly active antiretroviral therapy, an estimated 1%-5% of whom develop clinical hepatitis. We present a case of highly active antiretroviral therapy initiation for HIV that led to a flare of HBV activity despite antiviral therapy directed towards both. Liver biopsy and longitudinal serologic evaluation lend support to the hypothesis that the flare in activity was representative of IRIS. Importantly, we document eAg/eAb seroconversion with the IRIS phenomenon.

HIV-associated nephropathy: links, risks and management.

Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in APOL1 gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin–angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended.

Evolution of hepatitis C virus in HIV coinfected patients under antiretroviral therapy

Five patients (P) were followed-up for an average of 7.73years after highly active antiretroviral therapy (HAART) initiation. Patients' immune and virological status were determined by periodical CD4+T-cell counts and HIV and HCV viral load. HCV populations were studied using longitudinal high throughput sequence data obtained in parallel by virological and immunological parameters. Two patients (P7, P28) with sub-optimal responses to HAART presented HCV viral loads significantly higher than those recorded for two patients (P1, P18) that achieved good responses to HAART. Interestingly, HCV populations from P7 and P28 displayed a stable phylogenetic structure, whereas HCV populations from P1 and P18showeda significant increase in their phylogenetic structure, followed by a decrease after achieving acceptable CD4+T-cell counts (>500 cell/μl). The fifth patient (P25) presented high HCV viral loads, preserved CD4+T-cell counts from baseline and all along the follow-up, and displayed a constant viral phylogenetic structure. These results strongly suggest that HAART-induced immune recovery induces a decrease in HCV viral load and an increase in the HCV population phylogenetic structure likely reflecting the virus diversification in response to the afresh immune response. The relatively low HCV viral load observed in the HAART responder patients suggests that once HCV is adapted it reaches a maximum number of haplotypes higher than that achieved during the initial stages of the immune response as inferred from the two recovering patients. Future studies using larger number of patients are needed to corroborate these hypotheses.

Timing of Antiretroviral Treatment, Immunovirologic Status, and TB Risk: Implications for Testing and Treatment.

Tuberculosis (TB) risk and mortality increase in the 6 months after highly active antiretroviral therapy (HAART) initiation. This short-term risk may be a consequence of HAART initiation and immune reconstitution. Alternatively, it may be due to confounding by low CD4 counts and high HIV viral loads (VLs). We assessed the TB risk before and after HAART initiation while appropriately controlling for time-updated laboratory values and HAART exposure. We conducted an observational cohort study among persons enrolled in the North American AIDS Cohort Collaboration on Research and Design from 1998 through 2011. A marginal structural model was constructed to estimate the association of HAART initiation and TB risk. Inverse probability weights for the probability of HAART initiation were incorporated. Among 26,342 patients, 94 cases of TB were diagnosed during 147,557 person-years (p-y) of follow-up. The unadjusted TB rates were 93/100,000 p-y [95% confidence interval (CI): 63 to 132] before HAART initiation, 203/100,000 p-y (95% CI: 126 to 311) ≤6 months after HAART initiation, and 40/100,000 p-y (95% CI: 29 to 55) >6 months on HAART. After controlling for time-updated laboratory values, the adjusted odds of TB ≤6 months after HAART initiation and >6 months was 0.65 (95% CI: 0.28 to 1.51) and 0.29 (95% CI: 0.16 to 0.53), respectively. TB risk in the first 6 months after HAART initiation is not higher than that before HAART initiation after adjusting for CD4 count and VLs. These findings suggest that short-term TB risk may be related to low CD4 counts and high VLs near HAART initiation and support early HAART initiation to decrease TB risk.

Nutritional Status in People Living With HIV and Trends in HIV Prevalence Using NHANES (1999–2012)

BackgroundUnder‐nutrition is an independent predictor of mortality in people living with Human Immunodeficiency Virus (PLHIV). Introduction of the highly active antiretroviral therapy (ART) has improved the nutritional status in PLHIV but has not completely eliminated malnutrition.AimTo understand the current nutritional status in PLHIV and to study the trends in prevalence of HIV status using NHANES (1999–2012).MethodsNHANES 1999–2012 was used to estimate the prevalence of PLHIV in U.S. adults (n=16,083; ages 19–15) and for calculating selective biochemical parameters and biomarkers. Two 24‐hour dietary recalls were used to estimate energy adjusted mean values for micro‐ and macro‐nutrients; height and weight were used to calculate BMI.ResultsThe overall prevalence of HIV infection in U.S. adults was 0.44% (CI: 0.26–0.75) in 1999–2002, 0.53% (CI: 0.35–0.78) in 2003–2006, and started to decline thereafter to 0.25% (95% CI: 0.12–0.51) in the 2011–2012. HIV prevalence was highest in non‐Hispanic blacks followed by Mexican Americans and non‐Hispanic whites across all survey years. The mean age of PLHIV ranged from 35.4 years to 49.6 years. The body mass index (BMI) was lower in men and higher in women living with HIV compared to respective negative controls. Energy expenditure was significantly lower in women living with HIV compared to men living with HIV. Macronutrient intake was similar between PLHIV and HIV negative controls in both men and women. All the micronutrients were similar between PLHIV and controls except the levels of vitamin E was significantly lower in women living with HIV compared to the HIV negative controls. Micronutrient and macronutrient intake were similar between men and women living with HIV, except women had greater BMI and lower energy expenditure, while men had higher dietary fat intake. Women living with HIV had insufficient levels of vitamin D (37 nmol/L) and significantly lower levels of RBC folate (509 nmol/L) and Serum Folate (19 nmol/L). Mean triglycerides in men living with HIV was (410 mg/dL). There were no differences in the electrolyte levels and other biochemical markers compared to negative controls.ConclusionsWith the initiation of ART the nutrient intake in PLHIV has improved and is similar compared to HIV negative population. Women living with HIV have lower levels of vitamin D and folic acid. They have higher BMI and lower energy expenditure compared to men in spite of consuming similar quantities of micro‐ and micro‐nutrients, warranting life‐style modifications.

Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy.

Progressive multifocal leucoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML-IRIS in HIV-infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy. Single-center retrospective analysis of HIV-infected patients diagnosed with PML from 1996 to 2012 who received HAART. Among 59 PML patients treated with HAART, 18 (30.51%) developed PML-IRIS (five delayed PML-IRIS, 13 simultaneous PML-IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, P < 0.05) and experienced a greater decline in HIV-RNA levels in response to HAART (2.5log vs. 2.95log, P < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML-IRIS cases versus 2.56% of PML non-IRIS (P < 0.01). Survival rates were higher in patients with PML-IRIS compared to those with PML non-IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred. Nearly one-third of HIV-infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML-IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.

A relationship between CD4 count and oral manifestations of human immunodeficiency virus-infected patients on highly active antiretroviral therapy in urban population.

Introduction:Human immunodeficiency virus (HIV) infection gradually destroys the body's immune system, which makes it harder for the body to fight infections. HIV infection causes a quantitative and qualitative depletion of CD4 lymphocyte count, which increases the risk of opportunistic infections. Thus, CD4 count is one of the key factors in determining both the urgency of highly active antiretroviral therapy (HAART) initiation and the need of prophylaxis for opportunistic infections.Aim:This study aims to evaluate the prevalence and variations in the oral manifestations of HIV/acquired immune deficiency syndrome patients on HAART therapy in urban population and their association with CD4 count.Materials and Methods:A study was conducted by screening eighty patients who were HIV positive in an urban location. Both adult and pediatric patients were screened for oral manifestations and simultaneously CD4 count was also evaluated. Patients with HIV infection for variable time period who are under HAART were considered.Statistical Analysis:Measures of central tendency were used to analyse the data.Results:HIV infection destroys the immune system of an individual, making the patient susceptible to various infections and malignancies. With the advent of antiretroviral therapy, the scenario has changed drastically. We have observed that patients with CD4 counts between 164 and 1286 show relatively few oral manifestations. Long-term HAART therapy causes pigmentation, xerostomia and angular cheilitis but is taken up quite well by the patients.Conclusion:In this study, eighty patients with HAART from urban population showed very minimal oral findings because of good accessibility for treatment and awareness about HIV infections. The patients who were on long-standing HAART treatment also showed minimal oral manifestation such as pigmentation and xerostomia. Hence, we conclude that recognition, significance and treatment of these lesions in patients with HIV infection do not require elaborate setup and can be treated with basic primary health care.

Longitudinal Changes Over 10 Years in Free Testosterone Among HIV-Infected and HIV-Uninfected Men.

Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus are not known. HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed-effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus. One hundred eighty-two HIV-infected and 267 HIV-uninfected men were included, median age: 48.8 years (interquartile range: 45.8-53.4), median numbers of FT measurements per participant 4 (interquartile range: 3-5), 65% were drawn in the adjusted morning (AM). Mean-adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples {-6.1 ng/dL [95% confidence interval (CI): -9.8 to -2.4], P = 0.001}, but not in afternoon samples [-1.7 ng/dL (-6.0 to 2.6), P = 0.441]. The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: -13.4 to -5.0) per 10 years for HIV-infected vs. 7.9 ng/dL (95% CI: -10.2 to -5.5) for HIV-uninfected men, P = 0.578. FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not adjusted afternoon, FT levels among HIV-infected men compared with HIV-uninfected men suggest a loss of diurnal variation in FT levels among HIV-infected men.

Antiretroviral Treatment Efficacy and Safety in Older HIV-Infected Adults.

Highly active antiretroviral therapy (ART) and its widespread availability have revolutionized the landscape of HIV care and patient outcomes, transforming infection with HIV into a manageable chronic condition rather than a life-limiting disease. This transformation has created an older patient demographic. The effect that older age has on the outcomes of ART is not completely understood. Limited data are available in older individuals due to underrepresentation in clinical trials. To better understand this relationship, we conducted a literature search to assess the impact of older age on the outcomes of ART in the older HIV-infected population, including immunologic and virologic outcomes, mortality, disease progression, toxicity of ART, and pharmacokinetic considerations. In addition, package inserts of antiretroviral (ARV) medications were reviewed for efficacy, safety, and pharmacokinetic information pertaining to the older population. Most studies in older adults (50yrs or older) demonstrated slower and blunted CD4 immune recovery but better virologic suppression in response to ART. Higher rates of mortality and faster disease progression have been observed in adults 50 years and older, particularly during the first year after ART initiation. HIV-infected patients aged50years and older appear to be at greater risk for certain ART-associated toxicities including nephrotoxicity, decline in bone mineral density and bone fracture, symptomatic peripheral neuropathy, and cardiovascular disease including myocardial infarction. The available literature suggests that clinicians should consider avoiding agents such as tenofovir disoproxil fumarate (TDF) in older patients with risk factors for renal impairment and/or osteoporosis. If TDF is used in patients aged50years or older, more frequent monitoring should be considered. Older age was a significant predictor for higher atazanavir exposure and higher lopinavir trough concentration at 24weeks. The clinical implications of these findings are unknown. It is imperative that future development of novel ARV drug therapies includes a greater proportion of older subjects in clinical trials.

Cancer incidence among HIV-positive women in British Columbia, Canada: Heightened risk of virus-related malignancies.

We used population-based data to identify incident cancer cases and correlates of cancer among women living with HIV/AIDS in British Columbia (BC), Canada between 1994 and 2008. Data were obtained from a retrospective population-based cohort created from linkage of two province-wide databases: (1) the database of the BC Cancer Agency, a province-wide population-based cancer registry, and (2) a database managed by the BC Centre for Excellence in HIV/AIDS, which contains data on all persons treated with antiretroviral therapy in BC. This analysis included women (≥ 19 years old) living with HIV in BC, Canada. Incident cancer diagnoses that occurred after highly active antiretroviral therapy (HAART) initiation were included. We obtained a general population comparison of cancer incidence among women from the BC Cancer Agency. Bivariate analysis (Pearson χ(2) , Fisher's exact or Wilcoxon rank-sum test) compared women with and without incident cancer across relevant clinical and sociodemographic variables. Standardized incidence ratios (SIRs) were calculated for selected cancers compared with the general population sample. We identified 2211 women with 12 529 person-years (PY) of follow-up who were at risk of developing cancer after HAART initiation. A total of 77 incident cancers (615/100 000 PY) were identified between 1994 and 2008. HIV-positive women with cancer, in comparison to the general population sample, were more likely to be diagnosed with invasive cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma and Kaposi's sarcoma and less likely to be diagnosed with cancers of the digestive system. This study observed elevated rates of cancer among HIV-positive women compared to a general population sample. HIV-positive women may have an increased risk for cancers of viral-related pathogenesis.

Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome (IRIS) is characterized by improvement in a previously incompetent human immune system manifesting as worsening of clinical symptoms secondary to the ability of the immune system to now mount a vigorous inflammatory response. IRIS was first recognized in the setting of human immunodeficiency virus, and this clinical setting continues to be where it is most frequently encountered. Hallmarks of the pathogenesis of IRIS, independent of the clinical presentation and the underlying pathogen, include excessive activation of the immune system, with increased circulating effector memory T cells, and elevated levels of serum cytokines and inflammatory markers. Patients with undiagnosed opportunistic infections remain at risk for unmasking IRIS at the time of active antiretroviral therapy (ART) initiation. Systematic screening for opportunistic infections before starting ART is a key element to prevent this phenomenon. Appropriate management of IRIS requires prompt recognition of the syndrome and exclusion of alternative diagnoses, particularly underlying infections and drug resistance. Controlled studies supporting the use of pharmacologic interventions in IRIS are scare, and recommendations are based on case series and expert opinions. The only controlled trial published to date, showed reduction in morbidity in patients with paradoxical tuberculosis-related IRIS with the use of oral corticosteroids. There are currently limited data to recommend other anti-inflammatory or immunomodulatory therapies that are discussed in this review, and further research is needed. Ongoing research regarding the immune pathogenesis of IRIS will likely direct future rational therapeutic approaches and clinical trials.

No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception.

The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT. A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation. The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2). Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study

Whether the reported high risk of age-related diseases in HIV-infected people is caused by biological ageing or HIV-associated risk factors such as chronic immune activation and low-grade inflammation is unknown. We assessed time trends in age-standardised and relative risks of nine serious age-related diseases in a nationwide cohort study of HIV-infected individuals and population controls. We identified all HIV-infected individuals in the Danish HIV Cohort Study who had received HIV care in Denmark between Jan 1, 1995, and June 1, 2014. Population controls were identified from the Danish Civil Registration System and individually matched in a ratio of nine to one to the HIV-infected individuals for year of birth, sex, and date of study inclusion. Individuals were included in the study if they had a Danish personal identification number, were aged 16 years or older, and were living in Denmark at the time of study inclusion. Data for study outcomes were obtained from the Danish National Hospital Registry and the Danish National Registry of Causes of Death and were cardiovascular diseases (myocardial infarction and stroke), cancers (virus associated, smoking related, and other), severe neurocognitive disease, chronic kidney disease, chronic liver disease, and osteoporotic fractures. We calculated excess and age-standardised incidence rates and adjusted incidence rate ratios of outcomes for time after HIV diagnosis, highly active antiretroviral therapy (ART) initiation, and calendar time. The regression analyses were adjusted for age, sex, calendar time, and origin. We identified 5897 HIV-infected individuals and 53,073 population controls; median age was 36·8 years (IQR 30·6-44·4), and 76% were men in both cohorts. Dependent on disease, the HIV cohort had 55,050-57,631 person-years of follow-up and the population controls had 638,204-659,237 person-years of follow-up. Compared with the population controls, people with HIV had high excess and relative risk of all age-related diseases except other cancers. Overall, the age-standardised and relative risks of cardiovascular diseases, cancers, and severe neurocognitive disease did not increase substantially with time after HIV diagnosis or ART initiation. Except for chronic kidney diseases, the age-standardised and relative risks of age-related diseases did not increase with calendar time. Severe age-related diseases are highly prevalent in people with HIV, and continued attention and strategies for risk reduction are needed. The findings from our study do not suggest that accelerated ageing is a major problem in the HIV-infected population. Preben og Anna Simonsens Fond, Novo Nordisk Foundation, Danish AIDS Foundation, Augustinus Foundation, and Odense University Hospitals Frie Fonds Midler.