DNA Methylation Demonstrates Bronchoalveolar Cell Senescence in People Living with HIV: An Observational Cohort Study.

BACKGROUND: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging. METHODS: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10). RESULTS: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV. CONCLUSIONS: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.

Longitudinal evolution of the HIV effective reproduction number following sequential expansion of treatment as prevention and pre-exposure prophylaxis in British Columbia, Canada: a population-level programme evaluation.

BACKGROUND: Treatment as prevention and pre-exposure prophylaxis (PrEP) are key strategies in the control of HIV/AIDS. We aimed to characterise the longitudinal effects of antiretroviral therapy (ART), followed by treatment as prevention and the addition of PrEP, on the HIV effective reproduction number (Re) in British Columbia, Canada. METHODS: This population-level programme evaluation used data from the Drug Treatment Program of the British Columbia Centre for Excellence in HIV/AIDS (Vancouver, British Columbia, Canada). We also used estimates of HIV incidence and prevalence from the Public Health Agency of Canada, data on the number of new HIV diagnoses per year from the British Columbia Centre for Disease Control, and mortality data from the British Columbia Vital Statistics Agency. Data were obtained from 1985 until 2022, depending on the database source. Outcomes were the annual HIV prevalence, HIV incidence, number of new HIV diagnoses, number of people living with HIV on ART, HIV/AIDS-related and all-cause mortality rates, the HIV incidence-to-all-cause-mortality ratio, and Re. We calculated the modified effective reproduction number (Rme) using two thresholds of viral suppression and compared these values with Re. FINDINGS: We found a 95% decline in HIV/AIDS-related mortality and a 91% decrease in HIV incidence over the study period. The Re progressively declined from 1996 to 2022; however, from 1996 to 2017, Rme remained stable (>1) when calculated for people living with HIV with unsuppressed viraemia, suggesting that treatment as prevention reduces HIV incidence by decreasing the pool of individuals who are potentially able to transmit the virus. From 2018 to 2022, a decline in the estimated Re and Rme (<1) was observed regardless of whether we considered all people living with HIV or only those who were virologically unsuppressed. This finding suggests that PrEP decreases HIV incidence by reducing the number of susceptible individuals in the community, independently of viral suppression. INTERPRETATION: Our results show the synergy between generalised treatment as prevention and targeted PrEP in terms of decreasing HIV incidence. These findings support the incorporation of longitudinal monitoring of Re at a programmatic level to identify opportunities for the optimisation of treatment-as-prevention and PrEP programmes. FUNDING: British Columbia Ministry of Health, Health Canada, Public Health Agency of Canada, Vancouver Coastal Health, Vancouver General Hospital Foundation, Genome British Columbia, and the Canadian Institutes of Health Research.

Access to care and impact on HIV treatment interruptions during the COVID-19 pandemic among people living with HIV in British Columbia.

INTRODUCTION: The COVID-19 pandemic has changed healthcare service delivery. We examined the overall impact of COVID-19 on people living with HIV in British Columbia (BC), Canada, with a special focus on the potential impact of COVID-19 on antiretroviral treatment interruptions (TIs). METHODS: Purposive sampling was used to enrol people living with HIV aged ≥19 years across BC into the STOP HIV/AIDS Program Evaluation study between January 2016 and September 2018. Participants completed surveys at baseline enrolment and 18 and 36 months later. Additional COVID-19 questions were added to the survey in October 2020. TIs were defined as >60 days late for antiretroviral therapy (ART) refill using data from the BC HIV Drug Treatment Program. Generalized linear mixed models were used to examine trends in TIs over time and associations with reported health service access. RESULTS: Of 581 participants, 6.1%-7.7% experienced a TI during each 6-month period between March 2019 and August 2021. The frequency of TIs did not statistically increase during the COVID-19 epidemic. Among the 188 participants who completed the COVID-19 questionnaire, 32.8% reported difficulty accessing healthcare during COVID-19, 9.7% reported avoiding continuing a healthcare service due to COVID-19-related concerns, and 74.6% reported using virtual healthcare services since March 2020. In multivariable analysis, the odds of a TI in any 6-month period were not significantly different from March to August 2019. None of the reported challenges to healthcare services were associated with TIs. CONCLUSIONS: Although some participants reported challenges to accessing services or avoidance of services due to COVID-19, TIs were not more likely during COVID-19 than before.

The impact of the COVID-19 pandemic on HIV treatment gap lengths and viremia among people living with HIV British Columbia, Canada, during the COVID-19 pandemic: Are we ready for the next pandemic?

The SARS-CoV-2 (COVID-19) pandemic has impacted the care of people living with HIV (PLWH). This study aims to characterize the impact of the pandemic on the length of HIV treatment gap lengths and viral loads among people living with HIV (PLWH) in British Columbia (BC), Canada, with a focus on Downtown Eastside (DTES), which is one of the most impoverished neighbourhoods in Canada. We analyzed data from the HIV/AIDS Drug Treatment Program from January 2019 to February 2022. The study had three phases: Pre-COVID, Early-COVID, and Late-COVID. We compared results for individuals residing in DTES, those not residing in DTES, and those with no fixed address. Treatment gap lengths and viral loads were analyzed using a zero-inflated negative binomial model and a two-part model, respectively, adjusting for demographic factors. Among the 8982 individuals, 93% were non-DTES residents, 6% were DTES residents, and 1% had no fixed address during each phase. DTES residents were more likely to be female, with Indigenous Ancestry, and have a history of injection drug use. Initially, the mean number of viral load measurements decreased for all PLWH during the Early-COVID, then remained constant. Treatment gap lengths increased for all three groups during Early-COVID. However, by Late-COVID, those with no fixed address approached pre-COVID levels, while the other two groups did not reach Early-COVID levels. Viral loads improved across each phase from Pre- to Early- to Late-COVID among people residing and not residing in DTES, while those with no fixed address experienced consistently worsening levels. Despite pandemic disruptions, both DTES and non-DTES areas enhanced HIV control, whereas individuals with no fixed address encountered challenges. This study offers insights into healthcare system preparedness for delivering HIV care during future pandemics, emphasizing community-driven interventions with a particular consideration of housing stability.

T-Cell Responses to COVID-19 Vaccines and Breakthrough Infection in People Living with HIV Receiving Antiretroviral Therapy.

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccines, but fewer studies have examined cellular immune responses to the vaccinations. Here, we used an activation-induced marker (AIM) assay to quantify SARS-CoV-2 spike-specific CD4+ and CD8+ T cells generated by two and three doses of COVID-19 vaccines in 50 PLWH receiving antiretroviral therapy, compared to 87 control participants without HIV. In a subset of PLWH, T-cell responses were also assessed after post-vaccine breakthrough infections and/or receipt of a fourth vaccine dose. All participants remained SARS-CoV-2 infection-naive until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to a Nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 control participants after the third vaccine dose. Multivariable regression analyses were used to investigate the relationships between sociodemographic, health- and vaccine-related variables, vaccine-induced T-cell responses, and breakthrough infection risk. We observed that a third vaccine dose boosted spike-specific CD4+ and CD8+ T-cell frequencies significantly above those measured after the second dose (all p < 0.0001). Median T-cell frequencies did not differ between PLWH and controls after the second dose (p > 0.1), but CD8+ T-cell responses were modestly lower in PLWH after the third dose (p = 0.02), an observation that remained significant after adjusting for sociodemographic, health- and vaccine-related variables (p = 0.045). In PLWH who experienced a breakthrough infection, median T-cell frequencies increased even higher than those observed after three vaccine doses (p < 0.03), and CD8+ T-cell responses in this group remained higher even after a fourth vaccine dose (p = 0.03). In multivariable analyses, the only factor associated with an increased breakthrough infection risk was younger age, which is consistent with the rapid increase in SARS-CoV-2 seropositivity that was seen among younger adults in Canada after the initial appearance of the Omicron variant. These results indicate that PLWH receiving antiretroviral therapy mount strong T-cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.

Impact of screening and doxycycline prevention on the syphilis epidemic among men who have sex with men in British Columbia: a mathematical modelling study.

Background: Men who have sex with men (MSM) in British Columbia (BC) are disproportionately affected by infectious syphilis and HIV. In this study, we developed a co-interaction model and evaluated the impact and effectiveness of possible interventions among different MSM subgroups on the syphilis epidemic. Methods: We designed a deterministic compartmental model, which stratified MSM by HIV status and HIV pre-exposure prophylaxis (HIV-PrEP) usage into (1) HIV-negative/unaware MSM (HIV-PrEP not recommended, not on HIV-PrEP), (2) HIV-negative/unaware MSM with HIV-PrEP recommended (not on HIV-PrEP), (3) HIV-negative/unaware MSM actively on HIV-PrEP, and (4) MSM diagnosed with HIV. We estimated the effect of scaling up syphilis testing frequency from Status Quo to six-, four-, and three-months, increasing the percentage of MSM using doxycycline prevention (Doxy-P) to 25%, 50%, and 100% of the target level, and a combination of both among subgroups (2)-(4). We also assessed the impact of these interventions on the syphilis incidence rates from 2020 to 2034 in comparison to the Status Quo scenario where no intervention was introduced. Findings: Under the Status Quo scenario, with the expansion of the HIV-PrEP program to improve syphilis testing, the syphilis incidence rate was estimated to peak at 16.1 [Credible Interval (CI):14.2-17.9] per 1,000 person-years (PYs) in 2023 and decrease to 6.7 (CI:3.8-10.9) per 1,000 PYs by 2034. The syphilis incidence rate in 2034 was estimated at 0.7 (0.3-1.3) per 1,000 PYs if MSM diagnosed with HIV could be tested every four months, and at 1.5 (0.7-3.0) per 1,000 PYs if HIV-negative/unaware MSM actively on HIV-PrEP could be tested every three months. By achieving 100% of the target coverage of Doxy-P, the syphilis incidence rate was estimated at 1.4 (0.5-3.4) if focusing on MSM diagnosed with HIV, and 2.6 (1.2-5.1) per 1,000 PYs if focusing on HIV-negative/unaware MSM actively on HIV-PrEP. Under the combined interventions, the syphilis incidence rate could be as low as 0.0 (0.0-0.1) and 0.8 (0.3-1.8) per 1,000 PYs, respectively. Interpretation: The HIV-PrEP program in BC plays a crucial role in increasing syphilis testing frequency among high-risk MSM and reducing syphilis transmission among this group. In addition, introducing Doxy-P can be an effective complementary strategy to minimize syphilis incidence, especially among MSM diagnosed with HIV. Funding: This work was funded by the Canadian Institutes of Health Research.

Improved outcomes following gastrointestinal surgery among people living with HIV in the HAART-era: A scoping review.

BACKGROUND: This study aimed to review the varied 1-4 gastrointestinal (GI) system surgical outcomes among people living with Human Immunodeficiency Virus (PLWH) in the HAART-era. METHODS: MEDLINE and EMBASE were searched for primary publications on GI surgery outcomes exclusively in HAART-treated HIV patients. NSQIP-reported complications (NRCs), all-cause complications (ACC) and HIV disease parameters were extracted. RESULTS: 12 studies met study inclusion criteria, examining bowel (4), bariatric (5), cholecystectomy (1), appendectomy (1), and other general abdominal operations (1). The NRC rate was 0%, ≥44.4% and 13.3% in bariatric, bowel and appendix surgeries, respectively. Over half of NRCs were infectious. HAART-treated patients had lower ACC, LOS, and sepsis versus untreated-HIV, and higher ACC, LOS and reoperation rates versus HIV-negative patients. CONCLUSION: HAART use is associated with markedly improved NRC outcomes post GI surgery among PLWH; however, these remained inferior to those documented among HIV uninfected individuals.

Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size.

OBJECTIVE: The immunogenic nature of coronavirus disease 2019 (COVID-19) mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign. DESIGN: Longitudinal observational cohort and province-wide analysis. METHODS: Sixty-two participants were sampled prevaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the intact proviral DNA assay; pVL were measured using the cobas 6800 (lower limit of quantification: 20 copies/ml). The province-wide analysis included all 290 401 pVL performed in British Columbia, Canada between 2012 and 2022. RESULTS: Prevaccination, the median intact reservoir size was 77 [interquartile range (IQR): 20-204] HIV copies/million CD4 + T-cells, compared to 74 (IQR: 27-212) and 65 (IQR: 22-174) postfirst and -second dose, respectively (all comparisons P > 0.07). Prevaccination, 82% of participants had pVL <20 copies/ml (max: 110 copies/ml), compared to 79% postfirst dose (max: 183 copies/ml) and 85% postsecond dose (max: 79 copies/ml) ( P  > 0.4). There was no evidence that the magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike immune response influenced pVL nor changes in reservoir size ( P  > 0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART. CONCLUSION: We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia.

Using baseline CD4 cell count and plasma HIV RNA to guide the initiation of highly active antiretroviral therapy

Conflicting evidence regarding the impact of baseline plasma HIV RNA and CD4 cell count on survival after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients has resulted in wide variability in the expert recommendations regarding the when to start therapy. Early initiation of HAART may result in avoidable toxicities and premature evolution of resistance, whereas delaying HAART may increase the risk of opportunistic infections and/or preclude a worse virological and clinical response to therapy. While there is widespread consensus that HAART can be delayed to a CD4 cell count of 0.350 x 10 9 cells/L, the range between this threshold and 0.200 x 10 9 cells/L remains controversial. Greater uncertainty surrounds the role of baseline plasma HIV RNA, with some guidelines recommending initiating HAART when this level rises above 55,000 c/mL regardless of baseline CD4 cell count. The following review examines the evidence in support of delaying the initiation of HAART to a CD4 cell count of 0.200 x 10 9 cells/L regardless of plasma HIV RNA levels and outlines supporting data from a Canadian prospective cohort study of antiretroviral naïve patients treated with HAART. KEY WORDS. Plasma viral load. Adherence. Viral load supression. Virologic failure. Survival.

La carga viral plasmática y el nivel de los linfocitos CD4+ en la sangre son marcadores biológicos de alto valor pronóstico, en lo que se refiere a la historia natural de la infección por HIV. Esto ha sido demostrado en forma terminante en pacientes no tratados. El impacto y valor relativo de dichos marcadores en el pronóstico de pacientes que inician terapia antirretroviral no está totalmente aclarado. Esto ha generado opiniones diversas en la literatura médica, especialmente en lo que se refiere a las recomendaciones para el inicio del tratamiento en pacientes asintomáticos. Existe acuerdo general que el inicio del tratamiento se puede demorar hasta que los linfocitos CD4+ están en un nivel de 0.350 x 10 9 cells/L. Nuestros resultados, basados en una cohorte prospectiva canadiense, demuestran que es aceptable demorar el inicio del tratamiento hasta que los linfocitos CD4+ están en un nivel de 0.200 x 10 9 cells/L sin importar el nivel de la carga viral plasmática.

El estado actual del tratamiento de la infección por HIV / Present state of the treatment of HIV infection

La estrategia terapéutica antirretroviral cambió en 1996, al confirmarse el valor pronóstico de la carga viral plasmática y el recuento de linfocitos CD4+. Más recientemente se revisaron los lineamientos terapéuticos en favor de regímenes de tres drogas (dos nucleósidos y un inhibidor de las proteasas, o un no nucleósido) en forma exclusiva, con el objetivo de obtener la caída sostenida de la carga viral por debajo de 50 copias/ml. Ello ha dado lugar junto con una reconstitución del aparato inmune a la caída de la morbi-mortalidad asociada al SIDA. Se analizan las diferentes combinaciones de drogas empleadas en ensayos clínicos y sus resultados, las definiciones de fracaso terapéutico y sus consecuencias para el control del tratamiento. Con los esquemas actuales, el virus no es totalmente erradicado del organismo y los tratamientos deben continuarse de por vida. Las presentaciones combinadas de drogas en una misma tableta, y la disminución en el número de tomas diarias facilitan la adherencia del paciente y pueden permitir programas de tratamiento supervisado como los ya contemplados con éxito en tuberculosis. Se estudia actualmente la forma de disminuir los efectos adversos de estos regímenes. El uso de las pruebas de resistencia del virus y los fármacos facilita la selección del tratamiento más adecuado.

Diagnóstico, manejo y prevención de la neumonía por pneumocystis carinii asociada al sida / Diagnosis, management and prevention of AIDS-related pneumocystis carinii pneumonia

La neumonía por Pneumocystis carinii (PCP) se ha convertido en la más frecuente infección oportunista grave entre los infectados con VIH (más del 85 por ciento de los paceintes con SIDA presentan PCP durante el transcurso de su vida). Las características clínicas clásicas de la PCP son disnea, tos no productiva y fiebre. La insuficiencia respiratoria hipoxémica aguda que requiere ventilación mecánica puede ocurrir en hasta el 20 por ciento de los pacientes hospitalizados.El lavado broncolaveolar es un procedimiento rápido, seguro y efectivo para obtener una muestra adecuada para el diagnóstico microbiológico. Los pacientes con PCP leve a moderada son tratadops con la asociación Dapsona (DSP)-Trimetropin (TMP)por vía oral. Si hay preocupación acerca de una infección bacteriana secundaria, la asociación TMP-Sulfametoxazol (SMX) sería la mejor elección. La pentamidina debería reservarse para el tratamiento de pacientes hospitalizados con PCP comprobada microbiológicamente y para los casos con intolerancia a sulfonamidas. El tratamiento coadyuvante con corticoesteroides debería iniciarse de inmediato en cualquier paciente con una PaO2<70mmHg respirando aire ambiental. Un cambio en el agente antimicrobiano debería plantearse si no hay mejoría dentro de los primeros 7 días del tratamiento o bien si se desarrolla una reacción adversa grave a pesar del uso coadyuvante de corticoesteroides. La proporción de recaídas con PCP entre los pacientes con SIDA sobrepasa el 65 por ciento en un lapso de 18 meses. La profilaxis de la PCP ha sido exitosa con la asociación TMP-SMX (si es tolerada)o conla administración intermitente de pentamidina en aerosol. Debe iniciarse en pacientes con infección comprobada por VIH, cuando se tienen recuentos de CD4 bajo 250 células/mm3 sin considerar los síntomas o bien en cualquier momento después del primer episodio de PCP