Role of viral evolutionary rate in HIV-1 disease progression in a linked cohort

BACKGROUND: The actual relationship between viral variability and HIV disease progression and/or non-progression can only be extrapolated through epidemiologically-linked HIV-infected cohorts. The rarity of such cohorts accents their existence as invaluable human models for a clear understanding of molecular factors that may contribute to the various rates of HIV disease. We present here a cohort of three patients with the source termed donor A – a non-progressor and two recipients called B and C. Both recipients gradually progressed to HIV disease and patient C has died of AIDS recently. By conducting 15 near full-length genome (8.7 kb) analysis from longitudinally derived patient PBMC samples enabled us to investigate the extent of molecular factors, which govern HIV disease progression. RESULTS: Four time points were successfully amplified for patient A, 4 for patient B and 7 from patient C. Using phylogenetic analysis our data confirms the epidemiological-linkage and transmission of HIV-1 from a non-progressor to two recipients. Following transmission the two recipients gradually progressed to AIDS and one died of AIDS. Viral divergence, selective pressures, recombination, and evolutionary rates of HIV-1 in each member of the cohort were investigated over time. Genetic recombination and selective pressure was evident in the entire cohort. However, there was a striking correlation between evolutionary rate and disease progression. CONCLUSION: Non-progressing individuals have the potential to transmit pathogenic variants, which in other host can lead to faster HIV disease progression. This was evident from our study and the accelerated disease progression in the recipient members of he cohort correlated with faster evolutionary rate of HIV-1, which is a unique aspect of this study

Increasing HIV Subtype Diversity and Its Clinical Implications in a Sentinel North American Population

BACKGROUND: HIV-1 is a highly diverse virus; subtypes may exhibit differences in rates of transmission, disease progression, neurotoxicity, antiretroviral treatment failure profiles and accuracy of viral load measurements. To date, the HIV epidemic in Canada and the rest of the developed world has been largely due to subtype B; however, shifts in subtype epidemiology could have significant implications.OBJECTIVE: To determine whether there has been an increase in HIV subtype diversity in southern Alberta, Canada.METHODS: All 2358 patients receiving any HIV care between December 31, 2001 and December 31, 2010 were included in a retrospective analysis of subtype prevalence and incidence. In an indexed analysis, subtype trends from 1994 to 2010 were also evaluated.RESULTS: Between 2001 and 2010, the prevalence of non-B HIV subtypes in patients with a known subtype increased from 7% to 24%. In 2010, the most prevalent non-B subtypes were C (65%), A (11%), CRF02_AG (9.7%), CRF01_AE (4.9%), D (3.9%), G (2.9%) and CRF06_cpx (1.5%). In the indexed analysis, there was an overall proportional increase in non-B subtypes of 2.3% per year. The year-over-year increase in the prevalence of patients infected with a nonsubtype B virus increased from 13% from 1995 to 2002 to 27% from 2003 to 2010 (P=0.01). Incident non-B subtype cases increased from 9.6% to 32.4% over these time periods.CONCLUSIONS: This recent and dramatic shift in HIV strain diversity in Canada is unprecedented and may have important public health, research and clinical consequences.Peer Reviewe

Comparison of the RealTime HIV-1, COBAS TaqMan 48 v1.0, Easy Q v1.2, and Versant v3.0 assays for Determination of HIV-1 Viral Loads in a Cohort of Canadian Patients with Diverse HIV Subtype Infections▿

HIV clinics in Canada provide care to an increasing number of patients born outside of Canada with HIV-1 non-B subtype infections. Because the Easy Q HIV-1 v1.2 assay (EQ; bioMérieux) failed to detect some non-B subtype infections, a multiassay HIV-1 viral load (VL) study was conducted with patients with diverse HIV subtype infections. Patients were enrolled from the Southern Alberta HIV Clinic (SAC), Calgary, Alberta, Canada (n = 349) and the McGill HIV Clinic (MHC), Montreal, Quebec, Canada (n = 20) and had four or five tubes of blood drawn for testing by EQ and three other commercial HIV VL assays: (i) the Versant 3.0 HIV-1 test, with the Versant 440 instrument (branched DNA [bDNA]; Siemens), (ii) the RealTime HIV-1 test, with the m2000rt instrument (m2000rt; Abbott Molecular Diagnostics), and (iii) the COBAS AmpliPrep TaqMan HIV-1 48 test (CAP-CTM; Roche Molecular Diagnostics). Blood was processed according to the individual manufacturer's requirements and stored frozen at −86°C. The HIV subtype was known for patients who had undergone HIV genotypic resistance testing (Virco, Belgium). Data analyses were done using standard statistical methods within Stata 9.0 (StataCorp, College Station, TX). A total of 371 samples were tested on 369 patients, of whom 291 (81%) had a Virco genotype result of B (195; 53%) or non-B (96; 26%) subtypes A to D and F to K, as well as circulating recombinant forms (CRFs) (i.e., CRF01_AE and CRF02_AG). Most (58/78; 74%) patients of unknown subtype were recent African emigrants who likely have non-subtype B infection. Overall bias was small in pairwise Bland-Altman plots, but the limits of agreement between assays were wide. Discordant viral load results occurred for 98 samples and were due to missing values, false negatives, and significant underquantification that varied by HIV subtype. Results were obtained for all 371 samples with m2000rt, but for only 357 (97%) with CAP-CTM, 338 (92%) with EQ, and 276 (75%) with bDNA due to errors/equipment failures. False-negative results (nondetection of viral RNA versus other assay results) occurred for all platforms, as follows: for m2000rt, 8 (2%) [B(4) and non-B(4) subtypes], CAP-CTM, 9 (2.5%) [B(6) and non-B(3) subtypes]; EQ, 20 (6%) [B(7) and non-B(13) subtypes]; bDNA, 5 (2%) [B(1) and C(4)]. EQ and bDNA had the highest rates of underquantification by ≥1.0 log10 copies/ml, mainly for HIV non-B subtypes. Performance significantly varied between HIV VL platforms according to subtype. HIV viral diversity in the population being tested must be considered in selection of the viral load platform

COVID-19 vaccine uptake among people with HIV: identifying characteristics associated with vaccine hesitancy

Abstract People with HIV (PWH) are at increased risk of COVID-19 infection. Both Canadian (NACI) and US (CDC) guidelines recommend that all PWH receive at least 2 doses of COVID-19 vaccine, and a booster. We examined vaccination uptake among PWH in Southern Alberta, Canada. Among adult PWH, we evaluated COVID-19 vaccination uptake between December 2020 and August 2022. Poisson regression models with robust variance (approximating log binomial models) estimated crude and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for receiving (1) any vs. no vaccine, and (2) primary series with booster (≥ 3 vaccines) versus primary series without booster. Among 1885 PWH, 10% received no COVID-19 vaccinations, 37%  200 copies/mL), and using illegal substances. Factors associated with decreased booster uptake included being younger, Black (vs. White) ethnicity, substance use, lower educational attainment, and having an unsuppressed HIV viral load. COVID-19 booster uptake among PWH does not meet vaccine guidelines, and receipt of vaccines is unevenly distributed. Booster uptake is lowest among young females and marginalized individuals. Focused outreach is necessary to close this gap

Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries

BACKGROUND: Mortality in HIV-infected patients has declined substantially with combination antiretroviral therapy (ART), but it is unclear whether it has reached that of the general population. We compared mortality in patients starting ART in nine countries of Europe and North America with the corresponding general population, taking into account their response to ART. METHODS: Eligible patients were enrolled in prospective cohort studies participating in the ART Cohort Collaboration. We calculated the ratio of observed to expected deaths from all causes [standardized mortality ratio (SMR)], measuring time from 6 months after starting ART, according to risk group, clinical stage at the start of ART and CD4 cell count and viral load at 6 months. Expected numbers of deaths were obtained from age-, sex- and country-specific mortality rates. RESULTS: Among 29 935 eligible patients, 1134 deaths were recorded in 131 510 person-years of follow-up. The median age was 37 years, 8162 (27%) patients were females, 4400 (15%) were injecting drug users (IDUs) and 6738 (23%) had AIDS when starting ART. At 6 months, 23 539 patients (79%) had viral load measurements or=350 cells/microL and suppressed viral replication to 10 were 4, 14 and 47%. CONCLUSIONS: In industrialized countries, the mortality experience of HIV-infected patients who start ART and survive the first 6 months continues to be higher than in the general population, but for many patients excess mortality is moderate and comparable with patients having other chronic conditions. Much of the excess mortality might be prevented by earlier diagnosis of HIV followed by timely initiation of ART

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART