Starting Combination Antiretroviral Therapy Research Articles

Viral suppression and retention in HIV care during the postpartum period among women living with HIV: a longitudinal multicenter cohort study.

Low rates of postnatal retention in HIV care and viral suppression have been reported in women living with HIV (WLWH) despite viral suppression at delivery. At the same time, postpartum follow-up is of crucial importance in light of the increasing support offered in many resource-rich countries including Switzerland to WLWH choosing to breastfeed their infant, if optimal scenario criteria are met. We longitudinally investigated retention in HIV care, viral suppression, and infant follow-up in a prospective multicentre HIV cohort study of WLWH in the optimal scenario who had a live birth between January 2000 and December 2018. Risk factors for adverse outcomes in the first year postpartum were assessed using logistic and proportional hazard models. Overall, WLWH were retained in HIV care for at least six months after 94.2% of the deliveries (694/737). Late start of combination antiretroviral therapy (cART) during the third trimester was found to be the main risk factor for failure of retention in HIV care (crude odds ratio [OR] 3.91; 95% confidence interval [CI], 1.50-10.22; p=0.005). Among mothers on cART until at least one year after delivery, 4.4% (26/591) experienced viral failure, with illicit drugs use being the most important risk factor (hazard ratio [HR], 13.2; 95% CI, 2.35-73.6; p=0.003). The main risk factors for not following the recommendations regarding infant follow-up was maternal depression (OR, 3.52; 95% CI, 1.18-10.52; p=0.024). Although the results are reassuring, several modifiable risk factors for adverse postpartum outcome, such as late treatment initiation and depression, were identified. These factors should be addressed in HIV care of all WLWH, especially those opting to breastfeed in resource-rich countries. This study has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project 850 and by the SHCS research foundation.

Immune restoration affects 10-year survival in people living with HIV/AIDS.

In recent years, a reduction in the life expectancy gap between people living with HIV (PLWH) and the general population has been observed, irrespective of CD4 lymphocyte count, due to widespread access to antiretroviral treatment. The increase in the life expectancy of PLWH has increased awareness of both the ageing process and gender discrepancies in immune restoration and survival. Longitudinal data were collected for 2240 patients followed up at the Hospital for Infectious Diseases in Warsaw, Poland (n=1482), and the Department of Acquired Immunodeficiency, Pomeranian Medical University, Szczecin, Poland (n=758). Immune restoration was measured from the time of starting combination antiretroviral therapy until achieving 500 CD4 lymphocytes/μL, 800 CD4 lymphocytes/μL, and CD4/CD8 lymphocyte ratios of > 0.8 and > 1.0. Full recovery was achieved when the patient was restored to both 800 CD4 lymphocytes/μL and a CD4/CD8 lymphocyte ratio > 1.0. For all endpoints, immune restoration had a protective effect by reducing mortality. Patients who achieved immune restoration had a greater chance of reduced mortality than those who did not achieve immune restoration: for CD4 count > 500 cells/μL, HR=5.4 (interquartile range: 3.09-9.41), p < 0.001; for CD4 > 800 cells/μL, HR=5.37 (2.52-11.43), p < 0.001; for CD4/CD8 ratio > 0.8, HR=3.16 (1.81-5.51), p < 0.001; for CD4/CD8 ratio > 1.0, HR=2.67 (1.49-5.24), p=0.001, and for full immune recovery, HR=3.62 (1.63-8.04), p=0.002. Immune restoration remains a powerful factor in improving the survival of PLWH, regardless of the speed of recovery.

Incidence and factors associated with adverse drug reactions in a cohort of individuals starting dolutegravir or efavirenz

Prospective cohort of people living with HIV who started combination antiretroviral therapy (cART) with regimens containing efavirenz (EFV) or dolutegravir (DTG) in three specialized HIV/AIDS care services in Belo Horizonte, Brazil, with the objective of analyzing incidence, time to development and factors associated with the first adverse drug reaction (ADR). Data were collected from September 2015 to October 2018 through face-to-face interviews, clinical records, and information systems. The ADR-associated factors were evaluated with Cox regression and the time to the first ADR with Kaplan-Meier survival curves. Among the 433 individuals included, 217 (50.1%) had ADR in 12 months of follow-up. Among the 695 registered ADRs, 604 (86.9%) occurred in individuals using the EFV-based regimen, and gastrointestinal, psychiatric, and nervous system disorders were the most frequent. The mean time to develop the first ADR was 210.6 days (95% CI: 195.5-225.8). The concomitant use of other medications was associated with a higher risk of ADR (HR: 2.00; 95% CI: 1.38-2.89). The use of alcohol (HR: 0.64; 95% CI: 0.49-0.85) and the DTG-based regimen (HR: 0.40; 95% CI: 0.28-0.58) were factors associated with a lower risk of ADRs. We conclude that the DTG-based regimen had a better safety profile than the EFV-based regimen at 12 months of follow-up. Clinical and behavioral characteristics were associated with higher ADR risks and should be monitored when managing the treatment of HIV.

Life expectancy of people with HIV on long-term antiretroviral therapy in Europe and North America: a cohort study

BackgroundThe life expectancy of people with HIV starting combination antiretroviral therapy (ART) has increased substantially over the past 25 years. However, individuals treated before 1996 or with less effective and more toxic regimens than those currently available might have a worse prognosis. We estimated life expectancy from 2015 onwards, comparing people with HIV who started ART in different time periods since 1996. MethodsData were derived from 20 European and North American cohorts (Antiretroviral Therapy Cohort Collaboration and UK Collaborative HIV Cohort Study), for people with HIV who started potent ART after 1996 and were still on ART in 2015, or who started ART after 2015 and survived for at least 1 year. Follow-up started on or after Jan 1, 2015. Associations between mortality and demographic characteristics and biomarkers (CD4 and CD8 count in cells per μL and HIV-1 RNA viral load) at follow-up start were estimated using multivariable Poisson models. Estimated mortality rates in 5-year age bands were entered into life tables that contain follow-up information to estimate expected remaining life expectancy, stratified by sex and variables associated with mortality, and standardised to the proportion of people with HIV in each stratum. Life expectancy was compared with the French general population, as more data were available for France than for other countries included in the analyses. FindingsOf the 206 891 people with HIV eligible for inclusion from the cohort data, 5780 died during 619 356 person-years of follow-up after 2015. For women, the standardised remaining years of life expectancy at age 40 years for individuals starting ART between 1996 and 2014 was 36·0 years (95% CI 35·4–36·6), whereas it was 39·4 years (39·0–39·8) for individuals starting after 2015 (general population comparator 46·0 years). Corresponding figures for men were 34·7 years (34·1–35·3) and 37·2 years (36·6–38·8), respectively (general population comparator 40·3 years). For women starting ART between 1996 and 2014, with a CD4 count of 0–49 cells per μL at the commencement of follow-up, remaining life expectancy at age 40 years was 19·4 years (95% CI 18·2–20·6), rising to 40·4 years (40·0–40·8) for people with a CD4 count of 500 cells per μL or greater at commencement of follow-up. Corresponding figures for women starting ART after 2015 were 24·9 years (23·9–25·9) and 42·6 years (422–43·0), respectively. For men starting ART between 1996 and 2014 with a CD4 count of 0–49 cells per μL at commencement of follow-up, remaining life expectancy at age 40 years was 18·2 years (17·0–19·4), rising to 38·2 years (37·6–38·8) for men with a CD4 count of 500 cells per μL or more at commencement of follow-up. Corresponding remaining life expectancy for men starting ART after 2015 was 23·7 years (22·7–24·7) and 39·5 years (38·9–40·1), respectively. InterpretationFor people with HIV on long-term ART with high CD4 cell counts, life expectancies are estimated to be close to those of the general population, regardless of when they started ART. However, for people with HIV with low CD4 cell counts, estimates of remaining life expectancy are up to 30 years lower than in the general population, indicating the importance of early diagnosis and sustained treatment. FundingUS National Institute on Alcohol Abuse and Alcoholism, UK Medical Research Council.

Establishment of a miRNA profile in paediatric HIV-1 patients and its potential as a biomarker for effectiveness of the combined antiretroviral therapy

miRNAs have been extensively studied in pathological conditions, including viral infections, such as those provoked by HIV-1. Several cellular and circulating miRNAs are altered during HIV-1 infection, with either beneficial effects on host defenses or enhanced virus infectivity. Blood samples were collected in sterile EDTA tubes and plasma was separated and stored, as were PBMCs. RNA was isolated and reverse-transcribed. Finally, the miRNA gene expression profile was assessed using TaqMan Array Human microRNA Card A v2.0. A comprehensive statistical analysis was performed on the results obtained. This is the first study on miRNAs in HIV-1 paediatric patients, and a miRNA profile differentiating patients starting combination antiretroviral therapy (cART) at different times after HIV-1 diagnosis was established. Thirty-four miRNAs were observed to have different expression levels between the control group and the cART group. The data indicates the need to start cART as soon as possible after the establishment of HIV-1 infection to assure the best outcome possible. Finally, the selected 34 miRNAs may be used as biomarkers for prognosis and assessing therapy effectiveness. However, more research must be conducted to establish adequate quantitative correlations.

Development of HIV Drug Resistance in a Cohort of Adults on First-Line Antiretroviral Therapy in Tanzania during the Stavudine Era

As more HIV patients start combination antiretroviral therapy (cART), the emergence of HIV drug resistance (HIVDR) is inevitable. This will have consequences for the transmission of HIVDR, the success of ART, and the nature and trend of the epidemic. We recruited a cohort of 223 patients starting or continuing their first-line cART in Tanzania towards the end of the stavudine era in 2010. Patients were then followed for one year. Of those with a viral load test at baseline and follow-up time, 34% had a detectable viral load at the one-year endpoint. For 41 patients, protease and reverse transcriptase genotyping were successful. Eighteen samples were from cART-naïve patients, and 23 samples were taken under therapy either at baseline for cART-experienced patients or from follow-up samples for both cART–naïve and cART–experienced patients. The isolates were subtype A, followed by C and D in 41.5%, 22%, and 12.2% of the patients, respectively. No transmitted HIVDR was detected, as scored using the surveillance drug resistance mutations (DRMs) list. However, in 3 of the 18 samples from cART-naïve patients, the clinical Rega interpretation algorithm scored 44D or 138A as non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated polymorphisms. The most observed nucleoside reverse transcriptase inhibitor (NRTI) mutation was 184V. The mutation was found in 16 patients, causing resistance to lamivudine and emtricitabine. Nineteen patients had NNRTI resistance mutations, the most common of which was 103N, observed in eight patients. These high levels of resistance call for regular drug resistance surveillance in Tanzania to inform the control of the emergence and transmission of HIVDR.

Persistent Immune Activation in Human Immunodeficiency Virus-Infected Pregnant Women Starting Combination Antiretroviral Therapy After Conception.

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined.

Short Communication: No Significant Increase in Body Fat Mass in Naive HIV-Infected Patients Starting Raltegravir Plus Tenofovir Disoproxil Fumarate/Emtricitabine.

A significant weight gain has been reported in HIV-infected patients starting combination antiretroviral therapy (cART) including integrase strand transfer inhibitors, but clinical data about changes in body fat mass are still lacking. An observational retrospective analysis was made to evaluate changes in body fat mass and weight in 39 cART-naive patients initiating a first antiretroviral treatment, including tenofovir disoproxil fumarate/emtricitabine plus raltegravir (RAL) or darunavir/ritonavir (DRV/r), and who had a follow-up of at least 12 months and a whole-body dual-energy X-ray absorptiometry performed at baseline and after 12 months. After 12 months, changes in weight and total fat mass were comparable and statistically not significant in both groups. The median increase [interquartile range (IQR)] in weight was +2.02 kg (+1.19, +2.95; p = .378) in RAL group, and +1.71 kg (+0.89, +2.54; p = .449) in DRV/r group. The median increase in body fat mass (IQR) was +1.27 kg (+1.09, +1.43; p = .278) in RAL group, and +1.04 kg (+0.89, +1.22; p = .781) in DRV/r group. In conclusion, in our study, an initial regimen including RAL plus tenofovir/emtricitabine after 12 months led to a small and nonsignificant increase in weight and body fat mass, and changes were comparable with a DRV/r-based initial regimen.

IL7RA rs6897932 Polymorphism is Associated with Better CD4+ T-Cell Recovery in HIV Infected Patients Starting Combination Antiretroviral Therapy.

Interleukin-7 receptor subunit alpha (IL7RA) rs6897932 polymorphism IS related to CD4+ recovery after combination antiretroviral therapy (cART), but no studies so far have analyzed its potential impact in patients with very low CD4+ T-cells count. We aimed to analyze the association between IL7RA rs6897932 polymorphism and CD4+ T-cells count restoration in HIV-infected patients starting combination antiretroviral therapy (cART) with CD4+ T-cells count <200 cells/mm3. We performed a retrospective study in 411 patients followed for 24 months with a DNA sample available for genotyping. The change in CD4+ T-cells count during the follow-up was considered as the primary outcome. The rs6897932 polymorphism had a minimum allele frequency (MAF) >20% and was in Hardy–Weinberg equilibrium (p = 0.550). Of 411 patients, 256 carried the CC genotype, while 155 had the CT/TT genotype. The CT/TT genotype was associated with a higher slope of CD4+ T-cells recovery (arithmetic mean ratio; AMR = 1.16; p = 0.016), higher CD4+ T-cells increase (AMR = 1.19; p = 0.004), and higher CD4+ T-cells count at the end of follow-up (AMR = 1.13; p = 0.006). Besides, rs6897932 CT/TT was related to a higher odds of having a value of CD4+ T-cells at the end of follow-up ≥500 CD4+ cells/mm3 (OR = 2.44; p = 0.006). After multiple testing correction (Benjamini–Hochberg), only the increase of ≥ 400 CD4+ cells/mm3 lost statistical significance (p = 0.052). IL7RA rs6897932 CT/TT genotype was related to a better CD4+ T-cells recovery and it could be used to improve the management of HIV-infected patients starting cART with CD4+ T-cells count <200 cells/mm3.

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand.

To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy. Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration. Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last viral load at least 400 and first viral load less than 400 copies/ml. Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimen, respectively. At cART initiation, the median age, CD4% and viral load were 2.9 [interquartile range (IQR): 1.4-4.1] months, 34 (IQR: 24-45)% and 5.5 (IQR: 4.5-6.0) log10 copies/ml, respectively. Overall, an estimated 89% (95% confidence interval: 86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month older; P < 0.001], higher CD4% (aHR: 1.11 per 10% higher; P = 0.010) and lower log10 viral load (aHR: 0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression. We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long-term health.

Reactivity of Routine HIV Antibody Tests in Children With Perinatally Acquired HIV-1 in England: Cross-sectional Analysis.

We assessed HIV antibody prevalence in children with perinatally acquired HIV in England. Eighteen percent (10/55) of those starting combination antiretroviral therapy <6 months of age were seronegative at median age 9.1 years and had lower viral load at diagnosis and combination antiretroviral therapy start and fewer viral rebounds, than 45 of 55 seropositives. Implications for patient selection for HIV cure research, and interpretation of routine antibody testing, are discussed.

Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial.

Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy. EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%. Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, -100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level. In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART. NCT02551523.

Mitochondrial haplogroup H is related to CD4+ T cell recovery in HIV infected patients starting combination antiretroviral therapy

BackgroundThe mitochondrial DNA (mtDNA) seems to influence in a large number of diseases, including HIV infection. Moreover, there is a substantial inter-individual variability in the CD4+ recovery in HIV-infected patients on combination antiretroviral therapy (cART). Our study aimed to analyze the association between mtDNA haplogroups and CD4+ recovery in HIV-infected patients on cART.MethodsThis is a retrospective study of 324 naïve cART patients with CD4+ < 200 cells/mm3, who were followed-up during 24 months after initiating cART. All patients had undetectable HIV viral load during the follow-up. Besides, we included 141 healthy controls. MtDNA genotyping was performed by using Sequenom’s MassARRAY platform. The primary outcome variable was the slope of CD4+ recovery. Patients were stratified into two groups by the median slope value of CD4+ (9.65 CD4+ cells/mm3/month). Logistic regression analyses were performed to calculate the odds of CD4+ recovery according to mtDNA haplogroups.ResultsOur study included European HIV-infected patients within the N macro-cluster. The baseline values of CD4+ T-cells were similar between groups of patients stratified by the P50th of the slope of CD4+ T-cells recovery. Patients in the low CD4+ T-cells recovery group were older (p = 0.001), but this variable was included in the multivariate models. When we analyzed the frequencies of mtDNA haplogroups, no significant differences between HIV-infected individuals and healthy controls were found. We did not find any significant association between mtDNA haplogroups and the slope of CD4+ T-cells recovery by linear regression analysis. However, Patients carrying haplogroup H had a higher odds of having a better CD4+ recovery (> 9.65 CD4+ cells/mm3/month) than patients without haplogroup H (p = 0.032). The adjusted logistic regression showed that patients carrying haplogroup H had a higher likelihood of achieving a CD4+ recovery > 9.65 CD4+ cells/mm3/month [adjusted odds ratio (aOR) = 1.75 (95% CI = 1.04; 2.95); p = 0.035].ConclusionsEuropean mitochondrial haplogroup H was associated with the improved CD4+ recovery in HIV-infected patients starting cART with CD4+ < 200 cells/mm3.

Global temporal changes in the proportion of children with advanced disease at the start of combination antiretroviral therapy in an era of changing criteria for treatment initiation.

IntroductionThe CD4 cell count and percent at initiation of combination antiretroviral therapy (cART) are measures of advanced HIV disease and thus are important indicators of programme performance for children living with HIV. In particular, World Health Organization (WHO) 2017 guidelines on advanced HIV disease noted that >80% of children aged <5 years started cART with WHO Stage 3 or 4 disease or severe immune suppression. We compared temporal trends in CD4 measures at cART start in children from low‐, middle‐ and high‐income countries, and examined the effect of WHO treatment initiation guidelines on reducing the proportion of children initiating cART with advanced disease.MethodsWe included children aged <16 years from the International Epidemiology Databases to Evaluate acquired immunodeficiency syndrome (AIDS) (IeDEA) Collaboration (Caribbean, Central and South America, Asia‐Pacific, and West, Central, East and Southern Africa), the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE), the North American Pediatric HIV/AIDS Cohort Study (PHACS) and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 219C study. Severe immunodeficiency was defined using WHO guidelines. We used generalized weighted additive mixed effect models to analyse temporal trends in CD4 measurements and piecewise regression to examine the impact of 2006 and 2010 WHO cART initiation guidelines.ResultsWe included 52,153 children from fourteen low‐, eight lower middle‐, five upper middle‐ and five high‐income countries. From 2004 to 2013, the estimated percentage of children starting cART with severe immunodeficiency declined from 70% to 42% (low‐income), 67% to 64% (lower middle‐income) and 61% to 43% (upper middle‐income countries). In high‐income countries, severe immunodeficiency at cART initiation declined from 45% (1996) to 14% (2012). There were annual decreases in the percentage of children with severe immunodeficiency at cART initiation after the WHO guidelines revisions in 2006 (low‐, lower middle‐ and upper middle‐income countries) and 2010 (all countries).ConclusionsBy 2013, less than half of children initiating cART had severe immunodeficiency worldwide. WHO treatment initiation guidelines have contributed to reducing the proportion of children and adolescents starting cART with advanced disease. However, considerable global inequity remains, in 2013, >40% of children in low‐ and middle‐income countries started cART with severe immunodeficiency compared to <20% in high‐income countries.

Impact of HIV-1 subtype and Korean Red Ginseng on AIDS progression: comparison of subtype B and subtype D

BackgroundTo date, no study has described disease progression in Asian patients infected with HIV-1 subtype D. MethodsTo determine whether the disease progression differs in patients infected with subtypes D and B prior to starting combination antiretroviral therapy, the annual decline (AD) in CD4+ T cell counts over 96 ± 59 months was retrospectively analyzed in 163 patients and compared in subtypes D and B based on the nef gene. ResultsCD4+ T cell AD was significantly higher in the six subtype D–infected patients than in the 157 subtype B–infected patients irrespective of Korean Red Ginseng (KRG) treatment (p < 0.001). Of these, two subtype D–infected patients and 116 subtype B–infected patients had taken KRG. AD was significantly lower in patient in the KRG-treated group than in those in the KRG-naïve group irrespective of subtype (p < 0.05). To control for the effect of KRG, patients not treated with KRG were analyzed, with AD found to be significantly greater in subtype D–infected patients than in subtype B–infected patients (p < 0.01). KRG treatment had a greater effect on AD in subtype D–infected patients than in subtype B–infected patients (4.5-fold vs. 1.6-fold). Mortality rates were significantly higher in both the 45 KRG-naïve (p < 0.001) and all 163 (p < 0.01) patients infected with subtype D than subtype B. ConclusionSubtype D infection is associated with a >2-fold higher risk of death and a 2.9-fold greater rate of progression than subtype B, regardless of KRG treatment.

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ : CD8+ ratio.

Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+ : CD8+ ratio. Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+ : CD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+ : CD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. A total of 39 979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/μl, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+ : CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+ : CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/μl. A higher baseline CD4+ cell count predicted a shorter time to normalization. Declines in CD8+ cell count and increases in CD4+ : CD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+ : CD8+ ratio is strongly related to baseline CD4+ cell count.

The impact of HCV co-infection status on healthcare-related utilization among people living with HIV in British Columbia, Canada: a retrospective cohort study

BackgroundThe burden of HCV among those living with HIV remains a major public health challenge. We aimed to characterize trends in healthcare-related visits (HRV) of people living with HIV (PLW-HIV) and those living with HIV and HCV (PLW-HIV/HCV), in British Columbia (BC), and to identify risk factors associated with the highest HRV rates over time.MethodsEligible individuals, recruited from the BC Seek and Treat for Optimal Prevention of HIV/AIDS population-based retrospective cohort (N = 3955), were ≥ 18 years old, first started combination antiretroviral therapy (ART) between 01/01/2000–31/12/2013, and were followed for ≥6 months until 31/12/2014. The main outcome was HRV rate. The main exposure was HIV/HCV co-infection status. We built a confounder non-linear mixed effects model, adjusting for several demographic and time-dependent factors.ResultsHRV rates have decreased since 2000 in both groups. The overall age-sex standardized HRV rate (per person-year) among PLW-HIV and PLW-HIV/HCV was 21.11 (95% CI 20.96–21.25) and 41.69 (95% CI 41.51–41.88), respectively. The excess in HRV in the co-infected group was associated with late presentation for ART, history of injection drug use, sub-optimal ART adherence and a higher number of comorbidities. The adjusted HRV rate ratio for PLW-HIV/HCV in comparison to PLW-HIV was 1.18 (95% CI 1.13–1.24).ConclusionsAlthough HRV rates have decreased over time in both groups, PLW-HIV/HCV had 18% higher HRV than those only living with HIV. Our results highlight several modifiable risk factors that could be targeted as potential means to minimize the disease burden of this population and of the healthcare system.

Incidence and predictors of single drug discontinuation according to the presence of HCV coinfection in HIV patients from the ICONA Foundation Cohort Study

To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval [95%CI] 18.5-19.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01-2.22, p value = 0.045) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection.

The Safety of Substitution of Antiretroviral Regimen in Non-Clinical Trial Settings in Asian Countries

BackgroundAlthough substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the safety of substituting antiretroviral regimen in virologically suppressed HIV-infected patients in non-clinical trial settings in Asian countries.MethodsHIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD) were included in this analysis if they started combination antiretroviral therapy (cART) after 2002, were being treated at a center that documented a median rate of viral load (VL) monitoring ≥ 1 tests/patient/year, and experienced a minor or major treatment substitution while on virally suppressive cART (VL < 200 copies/mL). Minor regimen substitutions were defined as within-class changes and major regimen substitutions were defined as changes to a drug class. Virologic failure was defined as having had two viral load measurements > 400 copies/mL. The patterns of substitutions and rate of virologic failure after substitutions were analyzed.ResultsOf 3,994 adults who started ART after 2002, 3,119 (78.1%) had at least one period of virological suppression. Among these, 1,170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of virological failure were 1.48/100person years (95% CI 1.14–1.91) in the minor substitution group and 2.85/100person years (95% CI 1.88–4.33) in the major substitution group, and 2.53/100person years (95% CI 2.20–2.92) among patients that did not undergo a treatment substitution.ConclusionThe rate of virological failure was relatively low in both major and minor substitution groups, showing that regimen substitution is generally safe in non-clinical trial settings in Asian countries.Disclosures All authors: No reported disclosures.

White Matter Abnormalities in Children with HIV Infection and Exposure.

Background: Due to changes in guidelines and access to treatment, more children start combination antiretroviral therapy (ART) in infancy. With few studies examining the long-term effects of perinatal HIV infection and early ART on neurodevelopment, much is still unknown about brain maturation in the presence of HIV and ART. Follow-up studies of HIV infected (HIV+) children are important for monitoring brain development in the presence of HIV infection and ART.Methods: We use diffusion tensor imaging (DTI) to examine white matter (WM) in 65 HIV+ and 46 control (HIV exposed uninfected (HEU) and HIV unexposed uninfected (HU)) 7-year-old children. This is a follow up of a cohort studied at 5 years, where we previously reported lower fractional anisotropy (FA) in corticospinal tract (CST) and mean diffusivity (MD) increases in inferior/superior longitudinal fasciculi (ILF/SLF), inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus (UF) in HIV+ children compared to uninfected controls. In addition, we also found a difference in FA related to age at which ART was initiated.Results: At 7 years, we found two regions in the left IFOF and left ILF with lower FA in HIV+ children compared to controls. Higher MD was observed in a similar region in the IFOF, albeit bilaterally, as well as multiple clusters bilaterally in the superior corona radiata (SCR), the anterior thalamic radiation (ATR) and the right forceps minor. Unlike at 5 years, we found no impact on WM of ART initiation. In HEU children, we found a cluster in the right posterior corona radiata with higher FA compared to HU children, while bilateral regions in the CST demonstrated reduced MD.Conclusions: At age 7, despite early ART and viral load (VL) suppression, we continue to observe differences in WM integrity. WM damage observed at age 5 years persists, and new damage is evident. The continued observation of regions with lower FA and higher MD in HIV+ children point to disruptions in ongoing white matter development regardless of early ART. Lastly, in HEU children we find higher FA and lower MD in clusters in the CST tract suggesting that perinatal HIV/ART exposure has a long-term impact on WM development.