Cohort Of Antiretroviral Therapy Research Articles

Harmonization of alcohol use data and mortality across a multi-national HIV cohort collaboration.

Alcohol use is measured in diverse ways across settings. Harmonization of measures is necessary to assess effects of alcohol use in multi-cohort collaborations, such as studies of people with HIV (PWH). Data were combined from 14 HIV cohort studies (nine European, five North American) participating in the Antiretroviral Therapy Cohort Collaboration. We analyzed data on adult PWH with measured alcohol use at any time from 6 months before starting antiretroviral therapy. Five cohorts measured alcohol use with AUDIT-C and others used cohort-specific measures. We harmonized alcohol use as grams/day, calculated using country-level definitions of a standard drink. For Alcohol Use Disorders Identification Test (AUDIT-C), we used Items 1 (frequency) and 2 (number of drinks on a typical day). Where alcohol was measured in categories, we used the mid-point to calculate grams/day. We used multivariable Cox models to estimate associations of alcohol use with mortality. Alcohol use data were available for 83,424 PWH, 22,447 (27%) had AUDIT-C measures and 60,977 (73%) recorded the number of drinks/units per week/day. Of the sample, 19,150 (23%) were female, 54,006 (65%) had White ethnicity, and median age was 42 years. Median alcohol use was 0.3 g/day (interquartile range [IQR] 0-4.8) and 0 g/day (IQR 0-20) for those with and without AUDIT-C. There was a J-shaped relationship between grams/day and mortality, with higher mortality for PWH reporting no alcohol use (adjusted hazard ratio [aHR] 1.46; 95% CI: 1.23-1.72) and heavier (>61.0 g/day) alcohol use (aHR 1.92; 1.41-2.59) compared with 0.1-5.5 g/day among those with AUDIT-C measures. Associations were similar among those with non-AUDIT-C measures. Grams/day is a useful metric to harmonize diverse measures of alcohol use. Magnitudes of associations of alcohol use with mortality may differ by setting and measurement method. Higher mortality among those with heavier alcohol use strengthens the case for interventions to reduce drinking.

Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells.

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naïve PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH- B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH.

Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in treatment-naïve and treatment-experienced people with HIV: Findings from the Asia cohort of the BICSTaR study

BackgroundThe ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort. MethodsData were pooled from retrospective and prospective cohorts of antiretroviral therapy (ART)-naïve (hereafter, TN) and ART-experienced (hereafter, TE) people with HIV (aged ≥21 years) receiving B/F/TAF in routine clinical care in the Republic of Korea, Singapore, and Taiwan. Analyses included effectiveness (primary endpoint: HIV-1 RNA <50 copies/ml, missing = excluded analysis), CD4 count, CD4/CD8 ratio, safety, treatment persistence, and patient-reported outcomes (prospective group). ResultsThe analysis population included 328 participants (80 retrospective, 248 prospective; 65 TN, 263 TE). Participants were predominantly male (96.9% TN, 93.2% TE) with ≥1 comorbidity (52.3% TN, 57.8% TE); median age (years) was 31 (TN) and 42 (TE). Following 12 months of B/F/TAF, HIV-1 RNA was <50 copies/ml in 98.2% (54/55) of TN and 97.0% (227/234) of TE participants. Median (Q1, Q3) CD4 cell count increased by +187 (119, 291) cells/μl in the TN group (p < 0.001) and remained stable (+8 [–91, 110] cells/μl) in the TE group. B/F/TAF persistence was high in the prospective group, with 1/34 (2.9%) TN and 5/214 (2.3%) TE participants discontinuing treatment within 12 months. Drug-related adverse events occurred in 5.8% (19/328) of participants, leading to treatment discontinuation in 0.6% (2/328). ConclusionsReal-world evidence from BICSTaR supports the effectiveness, safety and tolerability of B/F/TAF in people with HIV in Asia.

Discrimination of the Veterans Aging Cohort Study Index 2.0 for Predicting Cause-specific Mortality Among Persons With HIV in Europe and North America.

Predicting cause-specific mortality among people with HIV (PWH) could facilitate targeted care to improve survival. We assessed discrimination of the Veterans Aging Cohort Study (VACS) Index 2.0 in predicting cause-specific mortality among PWH on antiretroviral therapy (ART). Using Antiretroviral Therapy Cohort Collaboration data for PWH who initiated ART between 2000 and 2018, VACS Index 2.0 scores (higher scores indicate worse prognosis) were calculated around a randomly selected visit date at least 1 year after ART initiation. Missingness in VACS Index 2.0 variables was addressed through multiple imputation. Cox models estimated associations between VACS Index 2.0 and causes of death, with discrimination evaluated using Harrell's C-statistic. Absolute mortality risk was modelled using flexible parametric survival models. Of 59 741 PWH (mean age: 43 years; 80% male), the mean VACS Index 2.0 at baseline was 41 (range: 0-129). For 2425 deaths over 168 162 person-years follow-up (median: 2.6 years/person), AIDS (n = 455) and non-AIDS-defining cancers (n = 452) were the most common causes. Predicted 5-year mortality for PWH with a mean VACS Index 2.0 score of 38 at baseline was 1% and approximately doubled for every 10-unit increase. The 5-year all-cause mortality C-statistic was .83. Discrimination with the VACS Index 2.0 was highest for deaths resulting from AIDS (0.91), liver-related (0.91), respiratory-related (0.89), non-AIDS infections (0.87), and non-AIDS-defining cancers (0.83), and lowest for suicides/accidental deaths (0.65). For deaths among PWH, discrimination with the VACS Index 2.0 was highest for deaths with measurable physiological causes and was lowest for suicide/accidental deaths.

Long-term effect of antiretroviral therapy on mortality among HIV-positive children and adolescents in China

IntroductionHighly active antiretroviral therapy (HAART) was piloted in 2002 and was scaled up in 2003 in mainland China. The aim of this study was to evaluate the mortality and its possible predictors based on the long-term initial antiretroviral therapy (ART) cohort among HIV positive children and adolescents. MethodsThis prospective open-labeled multicenter cohort study was conducted from January 2008 to July 2021. The participants were recruited from six representative sites in mainland China. A total of 609 participants with an HIV-positive serostatus and <18 years old were recruited and each participant was informed consent at the time of enrollment. Mortality and annual hazard were calculated, and predictors for death were analyzed using Cox regression models generating hazard ratios (HR). ResultsThe results showed that the mortality was 0.721 per hundred person-years, and the annual hazard was less than 0.10 over time. Both CD4+T cell count and CD4+T cell percentage declined in the death group during the follow-up. The Cox regression model showed that the baseline low CD4+T cell count level (Low vs. High: aHR = 8.309, 95% CI: (1.093, 63.135)) and age >5 years old at HIV diagnosis (6–12 vs. 0–5: aHR = 3.140, 95%CI: (1.331, 27.411)); 13–18 vs. 0–5: aHR = 5.451, 95%CI: (1.434, 20.724)) were possible risk factors for death. ConclusionThe longitudinal cohort study demonstrated the efficacy of China's ART program among HIV-positive children and adolescents which could be beneficial to other countries with limited resources.

Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes.

The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs. We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor-based regimen and cohort B started a protease inhibitor-based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as ≤20%. We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART. Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.

Estimation of Improvements in Mortality in Spectrum Among Adults With HIV Receiving Antiretroviral Therapy in High-Income Countries.

Mortality rates for people living with HIV (PLHIV) on antiretroviral therapy (ART) in high-income countries continue to decline. We compared mortality rates among PLHIV on ART in Europe for 2016-2020 with Spectrum's estimates. The AIDS Impact Module in Spectrum is a compartmental HIV epidemic model coupled with a demographic population projection model. We used national Spectrum projections developed for the 2022 HIV estimates round to calculate mortality rates among PLHIV on ART, adjusting to the age/country distribution of PLHIV starting ART from 1996 to 2020 in the Antiretroviral Therapy Cohort Collaboration (ART-CC)'s European cohorts. In the ART-CC, 11,504 of 162,835 PLHIV died. Between 1996-1999 and 2016-2020, AIDS-related mortality in the ART-CC decreased from 8.8 (95% CI: 7.6 to 10.1) to 1.0 (0.9-1.2) and from 5.9 (4.4-8.1) to 1.1 (0.9-1.4) deaths per 1000 person-years among men and women, respectively. Non-AIDS-related mortality decreased from 9.1 (7.9-10.5) to 6.1 (5.8-6.5) and from 7.0 (5.2-9.3) to 4.8 (4.3-5.2) deaths per 1000 person-years among men and women, respectively. Adjusted all-cause mortality rates in Spectrum among men were near ART-CC estimates for 2016-2020 (Spectrum: 7.02-7.47 deaths per 1000 person-years) but approximately 20% lower in women (Spectrum: 4.66-4.70). Adjusted excess mortality rates in Spectrum were 2.5-fold higher in women and 3.1-3.4-fold higher in men in comparison to the ART-CC's AIDS-specific mortality rates. Spectrum's all-cause mortality estimates among PLHIV are consistent with age/country-controlled mortality observed in ART-CC, with some underestimation of mortality among women. Comparing results suggest that 60%-70% of excess deaths among PLHIV on ART in Spectrum are from non-AIDS causes.

Health-related quality of life and hypertension in people with HIV on long-term antiretroviral therapy in Uganda.

The presence of hypertension could reduce the health-related quality of life (HRQoL) of people with HIV (PWH). Yet, literature describing the HRQoL of PWH who have hypertension in Uganda is scarce making the design of locally adapted interventions cumbersome. In our study, we compared HRQoL scores of people with HIV with and without hypertension on long term antiretroviral therapy (ART) in Uganda. We recruited 149 PWH with hypertension and 159 PWH without hypertension in the long-term ART cohort at an urban clinic in Kampala, Uganda. Data on socio-demographics were collected using an interviewer designed questionnaire while data on the World Health Organisation clinical stage viral load and CD4 count as well as ART duration were extracted from clinic electronic database and a generic EuroQol -5D- 5L (EQ-5D- 5L) and Medical Outcome Study (MOS-HIV) questionnaire used to collect HRQoL data. Data were summarized using descriptive statistics while inferential statistics were used to determine associations between key variables and HRQoL. Mann-Whitney U tests were used to compare HRQoL between groups of interest. One hundred ninety (61.7%) participants were female. PWH who had hypertension were older (Mean ± SD: 53.7 ± 8.3 vs 49.9 ± 8.6, p value <0.001) than those without hypertension. Participants with hypertension had lower overall median health utility scores (0.71 (0.33-0.80) vs 0.80 (0.44-0.80), p value = 0.029) and mean physical health score (48.44 ± 10.17 vs 51.44 ± 9.65, p value < 0.001) as opposed to those without hypertension. Hypertension (p value = 0.023), high income status, >70,000 UGX, (p value = 0.044), disclosure of the HIV status of the participants to their partner (p value = 0.026), and current history of smoking (p value = 0.029) were associated with low HRQoL scores. Among people with HIV, those with hypertension had lower HRQoL compared to those without. This calls for inclusion of quality-of-life assessment in the management of PWH who have been diagnosed with hypertension to identify those at risk and plan early interventions.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration

A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis

The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance. We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models. We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93-117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20-38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32-20·7) or intermediate or high-level (aOR 13·4, 4·55-39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance. Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART. US National Institutes of Health, Swiss National Science Foundation.

All-cause hospitalisation among people living with HIV according to gender, mode of HIV acquisition, ethnicity, and geographical origin in Europe and North America: findings from the ART-CC cohort collaboration

Understanding demographic disparities in hospitalisation is crucial for the identification of vulnerable populations, interventions, and resource planning. Data were from the Antiretroviral Therapy Cohort Collaboration (ART-CC) on people living with HIV in Europe and North America, followed up between January, 2007 and December, 2020. We investigated differences in all-cause hospitalisation according to gender and mode of HIV acquisition, ethnicity, and combined geographical origin and ethnicity, in people living with HIV on modern combination antiretroviral therapy (cART). Analyses were performed separately for European and North American cohorts. Hospitalisation rates were assessed using negative binomial multilevel regression, adjusted for age, time since cART intitiaion, and calendar year. Among 23 594 people living with HIV in Europe and 9612 in North America, hospitalisation rates per 100 person-years were 16·2 (95% CI 16·0-16·4) and 13·1 (12·8-13·5). Compared with gay, bisexual, and other men who have sex with men, rates were higher for heterosexual men and women, and much higher for men and women who acquired HIV through injection drug use (adjusted incidence rate ratios ranged from 1·2 to 2·5 in Europe and from 1·2 to 3·3 in North America). In both regions, individuals with geographical origin other than the region of study generally had lower hospitalisation rates compared with those with geographical origin of the study country. In North America, Indigenous people and Black or African American individuals had higher rates than White individuals (adjusted incidence rate ratios 1·9 and 1·2), whereas Asian and Hispanic people living with HIV had somewhat lower rates. In Europe there was a lower rate in Asian individuals compared with White individuals. Substantial disparities exist in all-cause hospitalisation between demographic groups of people living with HIV in the current cART era in high-income settings, highlighting the need for targeted support. Royal Free Charity and the National Institute on Alcohol Abuse and Alcoholism.

The impact of same-day antiretroviral therapy initiation on retention in care and clinical outcomes at four eThekwini clinics, KwaZulu-Natal, South Africa

BackgroundSame-day initiation (SDI) of antiretroviral therapy (ART) increases ART uptake, however retention in care after ART initiation remains a challenge. Public health behaviours, such as retention in HIV care and adherence to antiretroviral therapy (ART) pose major challenges to reducing new Human Immunodeficiency Virus (HIV) transmission and improving health outcomes among HIV patients.MethodsWe evaluated 6-month retention in care, and clinical outcomes of an ART cohort comprising of SDI and delayed ART initiators. We conducted a 6 months’ observational prospective cohort study of 403 patients who had been initiated on ART. A structured questionnaire was used to abstract data from patient record review which comprised the medical charts, laboratory databases, and Three Interlinked Electronic Registers.Net (TIER.Net). Treatment adherence was ascertained by patient visit constancy for the clinic scheduled visit dates. Retention in care was determined by status at 6 months after ART initiation.ResultsAmong the 403 participants enrolled in the study and followed up, 286 (70.97%) and 267 (66.25%) complied with scheduled clinics visits at 3 months and 6 months, respectively. One hundred and thirteen (28.04%) had been loss to follow-up. 17/403 (4.22%) had died and had been out of care after 6 months. 6 (1.49%) had been transferred to other health facilities and 113 (28.04%) had been loss to follow-up. Among those that had been lost to follow-up, 30 (33.63%) deferred SDI while 75 (66.37%) initiated ART under SDI. One hundred and eighty-nine (70.79%) participants who had remained in care were SDI patients while 78 (29.21%) were SDI deferred patients. In the bivariate analysis; gender (OR: 1.672; 95% CI: 1.002–2.791), number of sexual partners (OR: 2.092; 95% CI: 1.07–4.061), age (OR: 0.941; 95% CI: 0.734–2.791), ART start date (OR: 0.078; 95% CI: 0.042–0.141), partner HIV status (OR: 0.621; 95% CI: 0.387–0.995) and the number of hospitalizations after HIV diagnosis (OR: 0.173; 95% CI: 0.092–0.326). were significantly associated with viral load detection. Furthermore, SDI patients who defaulted treatment were 2.4 (95% CI: 1.165–4.928) times more likely to have increased viral load than those who had been returned in care.ConclusionViral suppression under SDI proved higher but with poor retention in care. However, the results also emphasise a vital need, to not only streamline processes to increase immediate ART uptake further, but also to ensure retention in care.

Retrospective analysis of a cohort of HIV-infected patients on antiretroviral therapy in Abidjan (2003 to 2017)

Background: Antiretroviral therapy (ART) has been successful in improving clinical outcomes for HIV-positive patients, but efforts are needed to improve life expectancy and quality of life. This study aimed to analyze a long-term ART cohort and assess patients' life expectancy. Methods: A retrospective cohort study was conducted at the infectious and tropical diseases department of the University Teaching Hospital of Treichville from 2003 to 2017. Data analysis was done using VBA access and XLSTAT 2018 excel software. Patients on post-exposure chemoprophylaxis and prevention of mother-to-child transmission were excluded. Results: Out of 19,567 patient records, 49.60% were included, 72.43% were in 1st line, and 50.10% were over 50 years old, mostly female 58.49%, 98.4% HIV1. 74.31% had a CD4/mm3 (Nadir) count &lt;350. The patients were essentially on the 2IN+INN regimen (72.31%), TDF + XTC + EFV (20.57%). The average duration under treatment 6.15 [0-13.67] ±3.94 years, the average duration under a line of treatment 4.33 [0-14.04] ±2.96 years. Life expectancy was 10.37 years. It is higher in patients on 2IN+IPr (12.21 years) versus 10.12 years in patients on 2IN+INN. The comparison of duration on a line according to the CD4 counts and the line of treatment did not show a significant difference p&gt;0.05. Conclusions: The study concluded that ART significantly improved the life expectancy of patients, adherence could be improved to further enhance the benefits of ART. The use of new combinations of ART may reduce events related to non-compliance.

Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies

The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.

Evaluation of treatment simplification strategies in patients living with HIV with multi-drug resistance.

Patients living with HIV (PLWH) with multi-drug resistance (MDR) and prior episodes of virologic failure have few therapeutic options remaining. These patients are often prescribed 'salvage' antiretroviral therapy (ART) regimens with high pill burdens, leading to potential decreased medication adherence and increased side effects and drug-drug interactions. In this retrospective, observational cohort study, we included adult patients with a diagnosis of HIV-1 who received care at our institution's Ryan White Clinic and who received 'salvage' ART, defined as three of more antiretroviral agents from at least three different HIV drug classes. Patients were grouped into two cohorts, simplified ART cohort and non-simplified ART cohort, based on whether their ART regimen was reduced by at least one tablet daily. The primary outcome was the percentage of patients who had their viral load suppressed (HIV-1 RNA <50 copies/ml) at their most recent clinic visit. Secondary outcomes were virologic failure (HIV-1 RNA ⩾200 copies/ml), percentage of time patients were virologically suppressed over the past 2 years, and the emergence of new treatment-resistant mutations. There were 50 patients included in the final analysis, 28 in the simplified ART cohort and 22 in the non-simplified ART cohort. The percentage of patients who had their HIV-1 viral load suppressed at their most recent clinic visit was n = 24 (86%) in the simplified ART cohort and n = 16 (73%) in the non-simplified ART cohort (p = 0.302). There were no statistically significant differences between the two cohorts in terms of the secondary outcomes. Our study found that simplification of ART regimens based on HIV genotype in PLWH with a history of MDR and prior virologic failures, regardless of the presence of HIV-1 viremia at the time of simplification, resulted in similar rates of virologic suppression and virologic failure as non-simplified ART regimens.

Re-evaluating the health impact and cost-effectiveness of tuberculosis preventive treatment for modern HIV cohorts on antiretroviral therapy: a modelling analysis using data from Tanzania

BackgroundIsoniazid preventive therapy (IPT) can prevent tuberculosis among people receiving antiretroviral therapy (ART). HIV programmes are now initiating patients on ART with higher average CD4 cell counts and lower tuberculosis risks under test-and-treat guidelines. We aimed to investigate how this change has affected the health impact and cost-effectiveness of IPT.MethodsWe constructed a tuberculosis–HIV microsimulation model parameterised using data from a large HIV treatment programme in Dar es Salaam, Tanzania. We simulated long-term health and cost outcomes for the 211 748 individuals initiating ART between Jan 1, 2014, and Dec 31, 2020, under three scenarios: no IPT access; observed levels of IPT access (75%) and completion (71%); and full (100%) IPT access and completion. We stratified results by ART initiation year and starting CD4 cell count.FindingsObserved levels of IPT access were estimated to have averted 12 800 (95% uncertainty interval 7300 to 21 600) disability-adjusted life-years (DALYs) and saved US$23 000 (–2 268 000 to 1 388 000). Full IPT access would have averted 24 500 (15 100 to 38 300) DALYs and cost $825 000 (–1 594 000 to 4 751 000), equivalent to $23·4 per DALY averted. Lifetime health benefits of IPT were estimated to be greater for more recent ART cohorts, while lifetime costs were stable. In subgroup analyses, a higher CD4 cell count at ART initiation was associated with greater health gains from IPT (15 900 [10 300 to 22 500] DALYs averted by full IPT per 100 000 patients for CD4 count >500 cells per μL at ART initiation, versus 7400 [4500 to 11 600] for CD4 count <100 cells per μL) and lower incremental lifetime costs.InterpretationIPT remains highly cost-effective or cost-saving for recent ART cohorts. The health impact and cost-effectiveness of IPT are estimated to improve as patients initiate ART earlier in the course of infection.FundingUS National Institutes of Health.

Declining Prevalence of Human Immunodeficiency Virus (HIV)-Associated Neurocognitive Disorders in Recent Years and Associated Factors in a Large Cohort of Antiretroviral Therapy-Treated Individuals With HIV.

HIV-associated neurocognitive disorders (HAND) have been suggested as persistent even with effective antiretroviral therapy (ART). Aims were to evaluate HAND prevalence and associated factors, in a large cohort of people-with-HIV (PWH). ART-treated PWH, underwent a neuropsychological examination through a battery of 12 tests exploring 5 different domains, between 2009 and 2020, were included in this cross-sectional analysis. HAND were classified according to Frascati's criteria. Participants were defined as complaining or not-complaining if a cognitive complaint was reported or not. Chi-square for trend and multivariable logistic regression were fitted. Overall, 1424 PWH were enrolled during four three-years periods. HAND prevalence was 24%; among complainers (572/1424), it was 38%, higher than among not-complainers (15%). Over the study period, a decreasing HAND prevalence was found in the entire population (P < 0.001) and in complaining (P < 0.001); in not-complaining it remained stable (P = 0.182). Factors associated with HAND were older age, lower educational level, lower current CD4+ T-cell count and HCV co-infection. Compared to nonnucleoside reverse transcriptase inhibitors, receiving dual and integrase strand transfer inhibitor (INSTI)-based therapies was associated with a decreased risk of HAND, as well as being tested in more recent years. In this large cohort of ART-treated PWH, mostly virologically suppressed, a remarkable decreasing HAND prevalence was observed. Besides HIV- and patient-related factors, the reduced risk of HAND found with dual and INSTI-based regimens along with a more recent ART initiation, could suggest a potential role of new treatment strategies in this decline, due to their greater virologic efficacy and better tolerability.

Effect of Late Testing and Antiretroviral Treatment on Mortality Among People Living With HIV in the Era of Treat-All in Guangdong Province, China, 1992-2018: A Cohort Study.

Late testing and antiretroviral therapy (ART) prevailed among people living with HIV (PLHIV) and impacted the benefit of immediate ART. This study aimed to identify the benefit of the test-and-immediate-treat policy in China, the effect of immediate ART, and the influence of late testing and ART on the whole PLHIV in Guangdong Province, China. We designed two tendency analyses in aggregative form and two cohorts (surveillance and ART cohort) in individuals' perspectives based on the HIV/AIDS Comprehensive Response Information Management System. Two interrupted time series models were conducted for tendency analysis from 2009 to 2018 to explore the all-cause and short-term mortality decrease after the test-and-immediate-treat policy. A time-dependent Cox model was performed for the surveillance cohort from 1992 to 2018 and a joint model was utilized for the ART cohort to identify the effect of immediate ART and the influence of late testing and ART on death. The tendency analysis included 324,914 and 68,679 person-year for all-cause/short-term mortality. A total of 49,289 and 26,287 PLHIV were recruited in the surveillance and ART cohort with 5,557 and 459 deaths, respectively. The short-term mortality dropped from 4.69 cases/100 person-year in January 2009 to 0.35 cases/100 person-year in December 2018 (standardized rate). The all-cause mortality saw a decreasing trend from 1.46 cases/100 person-year in January 2009 to 0.14 cases/100 person-year in December 2018 (standardized rate). The tendency analysis showed a significant short-term mortality slope decrease after the test-and-immediate-treat policy (P = 0.024). From the surveillance cohort, late testing, in general, was a risk factor for all-cause mortality [hazard ratio (HR) = 1.330, 95% CI, 1.250, 1.416]. ART cohort showed higher hazards of all-cause mortality among PLHIV with no late testing, but late ART (HR = 1.690, 95% CI, 1.166, 2.451) and both the late testing and late ART (HR = 1.335, 95% CI, 1.042, 1.710). Immediate ART might decrease the hazard of all-cause death though it is insignificant (HR = 0.923, 95% CI: 0.755, 1.129) in the ART cohort. The test-and-immediate-test policy brought benefit to PLHIV. We should enlarge HIV testing using comprehensive approaches to decrease late testing and ART and increase the benefit of immediate ART.

The Impact of Low-Level Viraemia on Virological Failure-Results From a Multicenter HIV Antiretroviral Therapy Cohort Study in Yunnan, China.

BackgroundHIV viral load (VL) is an important indicator to monitor treatment response in antiretroviral therapy (ART). Patients on ART may experience viral blips, with low-level elevations of VL between 50 and 999 copies/mL known as low-level viraemia (LLV), but not reaching the threshold for virological failure (≥1,000 copies/mL) defined by WHO guidelines. The objective was to investigate the long-term impact of LLV on virological failure.MethodsWe analyzed adults who were ART naïve at baseline. LLV was defined as having an VL of 51–999 copies/mL at least once. The subjects with LLV were grouped into three categories: 51–199, 200–399, and 400–999 copies/mL. Patients with multiple episodes of LLV were classified based on the highest VL result. The subjects with LLV were also grouped by the frequency of LLV, i.e., a single episode, two consecutive episodes, two intermittent episodes, more than two consecutive episodes, and more than two intermittent episodes. Multivariable Cox models were used to predict the association of LLV with virological failure.ResultsA total of 93,944 subjects were included. The median number of VL tests performed was 3. There were 21,203 LLV cases, with an overall incidence of 22.6%. Most of the LLV cases were found in subjects with LVs of 50–199 copies/mL, followed by 400–999 and 200–399 copies/mL. Most of the LLV cases experienced single episodes, and the numbers of LLV with two consecutive episodes, two intermittent episodes, more than two consecutive episodes and more than two intermittent episodes were decreased successively. The risk factors associated with virological failure include: intermediate-level (200–399 copies/mL) and high-level (400–999 copies/mL) LLV, single episodes of LLV and two or more than two consecutive episodes of LLV, which may put the subjects at a 1.28–2.26-fold higher risk for virological failure.ConclusionStrengthened immediate medical attention should be placed on patients with VL of 200–999 copies/mL. The patients having experienced LLV once should be targeted for case management and repeat VL testing within 24 weeks to determine persistent LLV and monitor virological failure.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BackgroundRegimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear.MethodsThis retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings.ResultsThere were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44–64] vs 42 years [IQR 35–50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5–8] vs 5 [IQR 4–6]), more co-medications (median 6 [IQR 4–11] vs 3 [IQR 2–7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%).ConclusionThe profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.