Comorbidities in Older Persons with Controlled HIV Infection: Correlations with Frailty Index Subtypes.

Frailty is prevalent in persons with human immunodeficiency virus (PWH), but factors predisposing older PWH to frailty remain uncertain. We examined factors associated with frailty and determined whether there were multiple frailty subtypes in older adults with controlled HIV infection. This was a cross-sectional outpatient study in an urban HIV clinic. Twenty-nine clinical indicators were extracted from medical records to compute a Frailty Index (FI) for 389 older (age 50+) PWH (range = 50-93; mean = 61.1, standard deviation = 7.2; 85% men) receiving HIV treatment in Calgary, Canada. We used regressions to identify factors associated with FI values. Latent class analysis was used to identify FI subtypes. Age, employment status, and duration of known HIV infection were the strongest predictors of FI (p's < 0.05). Four FI subtypes were identified. Subtype 1 (severe metabolic dysfunction+polypharmacy) had the highest mean FI (0.30). Subtype 2 (less severe metabolic dysfunction+polypharmacy) and Subtype 3 (lung and liver dysfunction+polypharmacy) had lower but equivalent mean FIs (0.20 for each). Subtype 4 (least severe metabolic dysfunction) had the lowest mean FI (0.13; p's < 0.001). Sociodemographic and behavioral characteristics differed among the subtypes. Individuals with Subtype 1 were older and more frequently unemployed/retired, whereas those with Subtype 3 were more likely to smoke, use crack/cocaine, have heavy alcohol use, and live in temporary/unstable housing. The clinical presentation of frailty in older PWH is heterogeneous. The metabolic syndrome, hepatitis C virus coinfection, cirrhosis, lung disease, and polypharmacy were associated with frailty as were unemployment/retirement, unstable housing, and substance use.

Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis.

BACKGROUND: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. METHODS: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. RESULTS: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. CONCLUSIONS: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes.

Sex-based differences in antiretroviral therapy initiation, switching and treatment interruptions: global overview from the International Epidemiologic Databases to Evaluate AIDS (IeDEA).

INTRODUCTION: In 2015, the World Health Organization recommended that all HIV-infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second-line regimens have not been well described. The aims of this study were to describe first-line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first-line ART, according to sex in each region. METHODS: Participating cohorts included: Southern, East and West Africa (IeDEA-Africa), North America (NA-ACCORD), Caribbean, Central/South America (CCASAnet) and Asia-Pacific including Australia (IeDEA Asia-Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first-line regimen. RESULTS AND DISCUSSION: The combined cohort data set comprised of 715,252 participants across seven regions from low- to high-income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV- positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low- and middle-income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. CONCLUSIONS: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex-specific factors such as pregnancy may contribute to these differences.

Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy.

OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. RESULTS: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. CONCLUSIONS: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes.

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts.

The changing demographics of women living with HIV/AIDS in southern Alberta from 1982 to 2006.

INTRODUCTION: Women account for a growing proportion of HIV infections in Canada. This has implications with respect to prevention, diagnosis and treatment. OBJECTIVE: To describe the female population presenting for HIV care in southern Alberta and to examine the impact of opt-out pregnancy screening. METHODS: A retrospective review of demographic and clinical characteristics of all patients presenting to the Southern Alberta HIV Clinic (SAC) care program from 1982 to 2006, was performed. RESULTS: The proportion of newly diagnosed patients who were female increased from 7.5% before 1998 to 21.5% after 1998. Women were more likely to be from vulnerable populations, such as intravenous drug users (31.3% versus 13.7%, P<0.001), aboriginals/Métis (21.5% versus 8.7%, P<0.001), blacks (28.9% versus 4.9%, P<0.001) and immigrants (36.6% versus 14.7%, P<0.001). Heterosexual intercourse was the main risk factor for HIV acquisition (43.7%). Women were less likely than men to have requested HIV testing (20.9% versus 37.8%, P<0.001). Opt-out pregnancy screening accounted for 12.7% of HIV-positive tests in women, following its introduction in 1998. Of the women diagnosed by pregnancy screening, 62.1% were from HIV-endemic countries. There was an association between reason for testing and CD4 count at presentation; women who requested their HIV test had higher median CD4 counts than those diagnosed because of illness (478 cells/mL, interquartile range [IQR]=370 cells/mL versus 174 cells/mL, IQR=328 cells/mL, P<0.001) or pregnancy screening (478 cells/mL, IQR=370 cells/mL versus 271 cells/mL, IQR=256 cells/mL, P=0.001). CONCLUSIONS: Women were less likely than men to have requested HIV testing and were more likely to be diagnosed by population-based screening methods. Women, especially vulnerable groups, account for a growing number and proportion of newly diagnosed HIV infections in Alberta. The implications of expanded screening in this population merit further consideration.

HISTORIQUE: Les femmes représentent une proportion croissante d'infections par le VIH au Canada. Ce constat a des conséquences sur la prévention, le diagnostic et le traitement. OBJECTIFS: Décrire la population de femmes consultant pour recevoir dessoins du VIH dans le sud de l'Alberta et examiner les conséquences du test de dépistage systématique pendant la grossesse. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des caractéristiques démographiques et cliniques de toutes les patientes qui avaient consulté au programme de soins de la clinique du VIH du sud de l'Alberta (CSA) entre 1982 et 2006. RÉSULTATS: La proportion de patientes nouvellement diagnostiquées est passée de 7,5 % avant 1998 à 21,5 % après 1998. Les femmes étaient plus susceptibles de provenir de populations vulnérables, telles que les consommatrices de drogues intraveineuses (31,3 % par rapport à 13,7 %, P<0,001), les Autochtones et les Métis (21,5 % par rapport à 8,7 %, P<0,001), les Noires (28,9 % par rapport à 4,9 %, P<0,001) et les immigrantes (36,6 % par rapport à 14,7 %, P<0,001). Les relations hétérosexuelles étaient le principal facteur de risque d'acquisition du VIH (43,7 %). Les femmes étaient moins susceptibles d'avoir demandé un test du VIH que les hommes (20,9 % par rapport à 37,8 %, P<0,001). Après la mise en œuvre du test de dépistage systématique pendant la grossesse en 1998, ce test représentait 12,7 % des tests positifs au VIH chez les femmes. Chez les femmes diagnostiquées au moyen de ce test, 62,1 % provenaient de pays endémiques au VIH. On constatait une association entre la raison de subir le test et la numération de CD4 à la présentation. Les femmes qui demandaient de subir le test du VIH présentaient une numération de CD4 médiane plus élevée que celles qui étaient diagnostiquées à cause d'une maladie (478 cellules/mL, écart interquartile [ÉIQ]=370 cellules/mL par rapport à 174 cellules/mL, ÉIQ=328 cellules/mL, P<0,001) ou d'un test pendant la grossesse (478 cellules/mL, ÉIQ=370 cellules/mL par rapport à 271 cellules/mL, ÉIQ=256 cellules/mL, P=0,001). CONCLUSIONS: Les femmes étaient moins susceptibles que les hommes d'avoir demandé un test de dépistage du VIH, mais plus susceptibles d'avoir été diagnostiquées par des méthodes de dépistage en population. Les femmes, en particulier les groupes vulnérables, représentent une proportion et un nombre croissant des nouvelles infections par le VIH en Alberta. Les conséquences d'un dépistage élargi au sein de cette population méritent un examen plus approfondi.

Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo.

BACKGROUND: Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy. METHODS: Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors. RESULTS: We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK-treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice. CONCLUSIONS: Z-FA-FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested.

The five-year impact of an evolving global epidemic, changing migration patterns, and policy changes in a regional Canadian HIV population.

OBJECTIVES: To evaluate the impact of policy changes to Canada's Immigration Act and changing migration patterns on a regional HIV population. METHODS: All HIV-positive individuals enrolled in care at the Southern Alberta Cohort between 2001 and 2007 were included and subdivided by self-reported country of birth. Demographic, clinical, and health utilization data were collected at each visit. We compare data and outcomes for each group and analyze changes since policy implementation. RESULTS: The proportion of immigrants/refugees increased significantly over the past five years. They present with lower CD4 counts, different HIV-subtypes, and previously rare co-morbidities. Management of disease progression necessitates more clinical visits and laboratory testing. Immigrants/refugees require greater social support to engage in, and to continue to access health care. Outcomes in HIV care were, however, equivalent to the Canadian-born population. CONCLUSIONS: The impact of changes to immigration policies is evident five years after implementation. Immigrant medical screening identifies increasing numbers of immigrants diagnosed with HIV. Immigrants require engagement in health care to achieve the full benefits of HIV management. Developed countries with increasing immigrant populations should be aware of how policy changes affect HIV prevalence rates, modes diagnosis and presentation, future clinical demands, and health care utilization.

Short communication: identification of a novel HIV type 1 subtype H/J recombinant in Canada with discordant HIV viral load (RNA) values in three different commercial assays.

The presence of HIV-1 non-B subtypes is increasing worldwide. This poses challenges to commercial diagnostic and viral load (RNA) monitoring tests that are predominantly based on HIV-1 subtype B strains. Based on phylogenetic analysis of the gag, pol, and env gene regions, we describe the first HIV-1 H/J recombinant in Canada that presented divergent viral load values. DNA sequence analysis of the gag gene region further revealed that genetic diversity between this H/J recombinant and the primers and probes used in the bio-Merieux Nuclisens HIV-1 QT (Nuclisens) and Roche Amplicor Monitor HIV-1, v1.5 (Monitor) viral RNA assays can erroneously lead to undetectable viral load values. This observation appears to be more problematic in the Nuclisens assay. In light of increasing genetic diversity in HIV worldwide we recommend that DNA sequencing of HIV, especially in the gag gene region targeted by primers and probes used in molecular diagnostic and viral load tests, be incorporated into clinical monitoring practices.

Full-length HIV type 1 genome analysis showing evidence for HIV type 1 transmission from a nonprogressor to two recipients who progressed to AIDS.

Epidemiologically-linked HIV-1 transmission cohorts serve as excellent models to study HIV disease progression. The actual relationship between viral variability and HIV disease outcome can be extrapolated only through such rare epidemiologically linked HIV-1-infected cohorts. We present here a cohort of three patients with the source termed donor A (a nonprogressor) and two recipients B and C. Both recipients acquired HIV through blood transfusion from donor A and have progressed to AIDS. By analyzing 15 near full-length HIV- 1 genomes (8.7 kb each genome) from longitudinally collected peripheral blood cell samples (four time points for patient A, four for patient B, and seven from patient C), we were able to demonstrate transmission of HIV from donor A and epidemiologic linkage among members A, B, and C after 10 years of HIV infection. These analyses are novel in demonstrating that HIV-1-infected nonprogressing individuals bear the potential to transmit HIV-1 variants and that HIV variants, which led to a benign disease in a nonprogressor donor, were able to cause disease in other individuals. Overall, these studies highlight the utility of full genome sequencing in establishing epidemiologic linkage in a chronically infected HIV cohort after 10 years of initial infection.