Stephen T. Wright

HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti‐HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy‐five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post‐LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence‐based typing and Luminex sequence‐specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA‐DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71–8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA‐DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46–27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64–5.72, p = 0.237). HLA‐A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor–recipient immune compatibility in LTx.

Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience

The aim of this study was to describe the long‐term changes in CD4 cell counts beyond 5 years of combination antiretroviral therapy (cART). If natural ageing leads to a long‐term decline in the immune system via low‐grade chronic immune activation/inflammation, then one might expect to see a greater or earlier decline in CD4 counts in older HIV‐positive patients with increasing duration of cART.

Rates and factors associated with major modifications to first-line combination antiretroviral therapy: results from the Asia-Pacific region.

Background In the Asia-Pacific region many countries have adopted the WHO’s public health approach to HIV care and treatment. We performed exploratory analyses of the factors associated with first major modification to first-line combination antiretroviral therapy (ART) in resource-rich and resource-limited countries in the region. Methods We selected treatment naive HIV-positive adults from the Australian HIV Observational Database (AHOD) and the TREAT Asia HIV Observational Database (TAHOD). We dichotomised each country’s per capita income into high/upper-middle (T-H) and lower-middle/low (T-L). Survival methods stratified by income were used to explore time to first major modification of first-line ART and associated factors. We defined a treatment modification as either initiation of a new class of antiretroviral (ARV) or a substitution of two or more ARV agents from within the same ARV class. Results A total of 4250 patients had 961 major modifications to first-line ART in the first five years of therapy. The cumulative incidence (95% CI) of treatment modification was 0.48 (0.44–0.52), 0.33 (0.30–0.36) and 0.21 (0.18–0.23) for AHOD, T-H and T-L respectively. We found no strong associations between typical patient characteristic factors and rates of treatment modification. In AHOD, relative to sites that monitor twice-yearly (both CD4 and HIV RNA-VL), quarterly monitoring corresponded with a doubling of the rate of treatment modifications. In T-H, relative to sites that monitor once-yearly (both CD4 and HIV RNA-VL), monitoring twice-yearly corresponded to a 1.8 factor increase in treatment modifications. In T-L, no sites on average monitored both CD4 & HIV RNA-VL concurrently once-yearly. We found no differences in rates of modifications for once- or twice-yearly CD4 count monitoring. Conclusions Low-income countries tended to have lower rates of major modifications made to first-line ART compared to higher-income countries. In higher-income countries, an increased rate of RNA-VL monitoring was associated with increased modifications to first-line ART.

CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts.

Objective:To examine CD4 cell responses to combination antiretroviral therapy (cART) in patients enrolled in the Australian HIV Observational Database who commenced cART at CD4 cell counts >350 cells per microliter. Methods:CD4 cell counts were modelled using random effects, repeated measurement models in 432 HIV-infected adults from Australian HIV Observational Database who commenced their first cART regimen and had a baseline CD4 count >350 cells per microliter. Using published AIDS and/or death incidence rates combined with the data summarized by time and predicted CD4 cell count, we calculated the expected reduction in risk of an event for different starting baseline CD4 strata. Results:Mean CD4 counts increased above 500 cells per microliter in all baseline CD4 strata by 12 months (means of 596, 717, and 881 cells/μL in baseline CD4 strata 351-500, 501-650, and >650 cells/μL, respectively) and after 72 months since initiating cART, mean CD4 cell counts (by increasing baseline CD4 strata) were 689, 746, 742 cells per microliter. The expected reduction in risk of mortality for baseline CD4 counts >650 cells per microliter relative to 351-500 cells per microliter was approximately 8%, an absolute risk reduction 0.33 per 1000 treated patient-years. Conclusions:Patients starting cART at high CD4 cell counts (>650 cells/μL) tend to maintain this immunological level over 6 years of follow-up. Patients starting from 351 to 500 CD4 cells per microliter achieve levels of >650 cells per microliter after approximately 3 years of cART. Initiating cART with a baseline CD4 count 501-650 or >650 cells per microliter relative to 351-500 cells per microliter indicated a minimal reduction in risk of AIDS incidence and/or death.

Determinants of viremia copy-years in people with HIV/AIDS after initiation of antiretroviral therapy

Background:Recent studies suggest higher cumulative HIV viremia exposure measured as viremia copy-years (VCY) is associated with increased all-cause mortality. The objectives of this study are (1) report the association between VCY and all-cause mortality and (2) assess associations between common patient characteristics and VCY. Methods:Analyses were based on patients recruited to the Australian HIV Observational Database (AHOD) who had received ≥24 weeks of antiretroviral therapy (ART). We established VCY after 1, 3, 5, and 10 years of ART by calculating the area under the plasma viral load time series. We used survival methods to determine the association between high VCY and all-cause mortality. We used multivariable mixed-effect models to determine predictors of VCY. We compared a baseline information model with a time-updated model to evaluate discrimination of patients with high VCY. Results:Of the 3021 AHOD participants who initiated ART, 2073 (69%), 1667 (55%), 1267 (42%), and 638 (21%) were eligible for analysis at 1, 3, 5, and 10 years of ART, respectively. Multivariable-adjusted hazard ratio association between all-cause mortality and high VCY was statistically significant, hazard ratio 1.52 (1.09, 2.13), P = 0.01. Predicting high VCY after 1 year of ART for a time-updated model compared with a baseline information model, the area under the sensitivity/specificity curve was 0.92 vs. 0.84; and at 10 years of ART, area under the sensitivity/specificity curve was 0.87 vs. 0.61, respectively. Conclusion:A high cumulative measure of viral load after initiating ART is associated with increased risk of all-cause mortality. Identifying patients with high VCY is improved by incorporating time-updated information.

HIV and aging: Insights from the Asia Pacific HIV Observational Database (APHOD)

The proportion of people living with HIV/AIDS in the ageing population (> 50 years old) is increasing. We aimed to explore the relationship between older age and treatment outcomes in HIV‐positive persons from the Asia Pacific region.

How do outcomes compare between women and men living with HIV in Australia? An observational study

UNLABELLED Background Gender differences vary across geographical settings and are poorly reported in the literature. The aim of this study was to evaluate demographics and clinical characteristics of participants from the Australian HIV Observational Database (AHOD), and to explore any differences between females and males in the rate of new clinical outcomes, as well as initial immunological and virological response to antiretroviral therapy. METHODS Time to a new clinical end-point, all-cause mortality and/or AIDS illness was analysed using standard survival methods. Univariate and covariate adjusted Cox proportional hazard models were used to evaluate the time to plasma viral load suppression in all patients that initiated antiretroviral therapy (ART) and time to switching from a first-line ART to a second-line ART regimen. RESULTS There was no significant difference between females and males for the hazard of all-cause mortality [adjusted hazard ratio: 0.98 (0.51, 1.55), P=0.67], new AIDS illness [adjusted hazard ratio: 0.75 (0.38, 1.48), P=0.41] or a composite end-point [adjusted hazard ratio: 0.74 (0.45, 1.21), P=0.23]. Incident rates of all-cause mortality were similar between females and males; 1.14 (0.61, 1.95) vs 1.28 (1.12, 1.45) per 100 person years. Virological response to ART was similar for females and males when measured as time to viral suppression and/or time to virological failure. CONCLUSION This study supports current Australian HIV clinical care as providing equivalent standards of care for male and female HIV-positive patients. Future studies should compare ART-associated toxicity differences between ART-associated toxicity differences between men and women living with HIV in Australia.

Subsidized optimal ART for HIV-positive temporary residents of Australia improves virological outcomes: results from the Australian HIV Observational Database Temporary Residents Access Study

HIV‐positive (HIV+) temporary residents living in Australia legally are unable to access government subsidized antiretroviral treatment (ART) which is provided via Medicare to Australian citizens and permanent residents. Currently, there is no information systematically being collected on non‐Medicare eligible HIV+ patients in Australia. The objectives of this study are to describe the population recruited to the Australian HIV Observational Database (AHOD) Temporary Residents Access Study (ATRAS) and to determine the short‐ and long‐term outcomes of receiving (subsidized) optimal ART and the impact on onwards HIV transmission.

Temporal trends of time to antiretroviral treatment initiation, interruption and modification: examination of patients diagnosed with advanced HIV in Australia

HIV prevention strategies are moving towards reducing plasma HIV RNA viral load in all HIV‐positive persons, including those undiagnosed, treatment naïve, on or off antiretroviral therapy. A proxy population for those undiagnosed are patients that present late to care with advanced HIV. The objectives of this analysis are to examine factors associated with patients presenting with advanced HIV, and establish rates of treatment interruption and modification after initiating ART.

Treatment and disease outcomes of migrants from low- and middle-income countries in the Australian HIV Observational Database cohort

ABSTRACT People from culturally and linguistically diverse backgrounds, including low- and middle-income countries, account for a third of new HIV diagnoses in Australia and are a priority for HIV prevention and treatment programs. We describe the demographic and clinical characteristics of participants in the Australian HIV Observational Database (AHOD) and compare disease outcomes, progression to AIDS and treatment outcomes of those born in low- and middle-income countries, with those born in high-income countries and Australia. All participants enrolled in AHOD sites where country of birth is routinely collected were included in the study. Age, CD4 count, HIV viral load, antiretroviral therapy, hepatitis co-infection, all-cause mortality and AIDS illness were analysed. Of 2403 eligible participants, 77.3% were Australian born, 13.7% born in high-income countries and 9.0% born in middle- or low-income countries. Those born in Australia or high-income countries were more likely to be male (96%) than those from middle- or low-income countries (76%), p < .0001 and more likely to have acquired HIV via male to male sexual contact (77%; 79%) compared with those from middle- or low-income countries (50%), p < .0001. At enrolment, mean CD4 cell count was higher in Australian born (528 cells/µL) than both those born in high-income countries (468 cells/µL) and those born in middle- and low-income countries (451 cells/µL), p < .0001; whereas the mean HIV RNA level (log10 copies/mL) was similar in all three groups (4.44, 4.76 and 4.26, respectively), p = .19.There was no difference in adjusted incidence risk ratios for all-cause mortality and AIDS incidence in all three groups, p = .39. These findings reflect successful outcomes of people born in low- and middle-income countries once engaged in HIV care.