Showing papers by "Gilles Wandeler published in 2023"

Systematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa

Abstract: Abstract In sub-Saharan Africa, simple biomarkers of liver fibrosis are needed to scale-up hepatitis B treatment. We conducted an individual participant data meta-analysis of 3,548 chronic hepatitis B patients living in eight sub-Saharan African countries to assess the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index and two other fibrosis biomarkers using a Bayesian bivariate model. Transient elastography was used as a reference test with liver stiffness measurement thresholds at 7.9 and 12.2kPa indicating significant fibrosis and cirrhosis, respectively. At the World Health Organization-recommended cirrhosis threshold (>2.0), aspartate aminotransferase-to-platelet ratio index had sensitivity (95% credible interval) of only 16.5% (12.5–20.5). We identified an optimised aspartate aminotransferase-to-platelet ratio index rule-in threshold (>0.65) for liver stiffness measurement >12.2kPa with sensitivity and specificity of 56.2% (50.5–62.2) and 90.0% (89.0–91.0), and an optimised rule-out threshold (<0.36) with sensitivity and specificity of 80.6% (76.1–85.1) and 64.3% (62.8–65.8). Here we show that the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index threshold is inappropriately high in sub-Saharan Africa; improved rule-in and rule-out thresholds can optimise treatment recommendations in this setting.

Impact of integrase inhibitors on cardiovascular disease events in people with HIV starting antiretroviral therapy.

Abstract: BACKGROUND Integrase strand transfer inhibitors (INSTI) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with HIV (PWH) using a target trial framework, which reduces the potential for confounding and selection bias. METHODS We included Swiss HIV Cohort Study participants who were ART-naïve after 05/2008, when INSTI became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs. other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (IQR 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increase in CVD events (adjusted hazard ratio 0.80, 95% confidence interval [CI] 0.46-1.39). Adjusted risk differences between individuals who started INSTI and those who started other ART were -0.17% (95% CI -0.37-0.19) after one year, -0.61% (-1.54-0.22) after 5 years, and -0.71% (-2.16-0.94) after 8 years. CONCLUSIONS In this target trial emulation, we found no difference in short or longer term risk for CVD events between treatment-naïve PWH who started INSTI-based and those on other ART.

Hepatitis delta infection among persons living with HIV in Europe

Abstract: A high prevalence of hepatitis delta virus (HDV) infection, the most severe form of viral hepatitis, has been reported among persons living with HIV (PLWH) in Europe. We analysed data from a large HIV cohort collaboration to characterize HDV epidemiological trends across Europe, as well as its impact on clinical outcomes.

Cryptococcal Meningitis and Clinical Outcomes in Persons with HIV: A Global View.

Abstract: BACKGROUND Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with HIV(PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. METHODS This retrospective cohort study investigated CM incidence and all-cause mortality after CM diagnosis in PWH in the IeDEA cohort from 1996-2017. We estimated overall and region-specific incidence and incidence rate ratios using quasi-Poisson models adjusted for sex, age, calendar year, time-updated CD4, and time-updated antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. RESULTS Among 518,852 PWH, there were 3,857 diagnosed cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. 2,478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (HR 1.31 for 50 vs 35 years; 95%CI 1.12-1.53), lower CD4 (HR 1.15 for 200 vs 350 cells/mm3; 95%CI 1.03-1.30), and earlier year of CM diagnosis (HR 0.51 for 2015 vs 2000; 95%CI 0.37-0.70) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. CONCLUSIONS Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

Viral suppression and retention in HIV care during the postpartum period among women living with HIV: a longitudinal multicenter cohort study

Abstract: Low rates of postnatal retention in HIV care and viral suppression have been reported in women living with HIV (WLWH) despite viral suppression at delivery. At the same time, postpartum follow-up is of crucial importance in light of the increasing support offered in many resource-rich countries including Switzerland to WLWH choosing to breastfeed their infant, if optimal scenario criteria are met. We longitudinally investigated retention in HIV care, viral suppression, and infant follow-up in a prospective multicentre HIV cohort study of WLWH in the optimal scenario who had a live birth between January 2000 and December 2018. Risk factors for adverse outcomes in the first year postpartum were assessed using logistic and proportional hazard models. Overall, WLWH were retained in HIV care for at least six months after 94.2% of the deliveries (694/737). Late start of combination antiretroviral therapy (cART) during the third trimester was found to be the main risk factor for failure of retention in HIV care (crude odds ratio [OR] 3.91; 95% confidence interval [CI], 1.50–10.22; p = 0.005). Among mothers on cART until at least one year after delivery, 4.4% (26/591) experienced viral failure, with illicit drugs use being the most important risk factor (hazard ratio [HR], 13.2; 95% CI, 2.35–73.6; p = 0.003). The main risk factors for not following the recommendations regarding infant follow-up was maternal depression (OR, 3.52; 95% CI, 1.18–10.52; p = 0.024). Although the results are reassuring, several modifiable risk factors for adverse postpartum outcome, such as late treatment initiation and depression, were identified. These factors should be addressed in HIV care of all WLWH, especially those opting to breastfeed in resource-rich countries. This study has been financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project 850 and by the SHCS research foundation.

HBV viral replication markers and hepatic fibrosis in untreated chronic HBV infection with and without HIV coinfection in Zambia.

Abstract: BACKGROUND To inform novel therapies, a more nuanced understanding of HIV's impact on hepatitis B virus (HBV) natural history is needed, particularly in high burden countries. METHODS In Lusaka, Zambia, we compared prospectively-recruited adults (18+ years) with chronic HBV infection, with and without HIV, pre-therapy. We excluded those with treatment-experience or HBV diagnosis due to clinical suspicion. We assessed HBV DNA levels, hepatitis B e antigen, CD4 (if coinfection), and liver disease (transient elastography [TE], serum alanine aminotransferase). In multivariable analyses, we evaluated the association of HIV overall and by level of CD4 count on these markers. RESULTS Among 713 adults analyzed, median age was 33 years, 63.0% were male, and 433 had HBV/HIV coinfection. Median CD4 count was 200 cells/mm3. HBV DNA was >2,000 IU/ml for 311 (51.0%) and 227 (32.5%) were HBeAg-positive. 15.5% had advanced fibrosis or cirrhosis. HIV coinfection was associated with 5-fold increased HBV DNA levels (adjusted geometric mean ratio, 5.78; 95% confidence interval, 2.29-14.62) and 2 times the odds of HBeAg-positivity (adjusted odds ratio, 2.54; 95% CI, 1.59-4.08). These associations were significant only at CD4 counts 100-350 and <100 cells/mm3. HIV was not associated with markers of fibrosis or ALT. DISCUSSION HIV's impact on HBV natural history likely depends on the degree and duration of immune suppression. There is strong rationale to monitor HBV DNA in people with HBV/HIV coinfection and immune suppression. A better understanding is needed of mechanisms of increased liver-related mortality in people with HBV/HIV coinfection.

Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods

Abstract: While combination therapy completely suppresses HIV-1 replication in blood, functional virus persists in CD4+ T cell subsets in non-peripheral compartments that are not easily accessible. To fill this gap, we investigated tissue-homing properties of cells that transiently appear in the circulating blood. Through cell separation and in vitro stimulation, the HIV-1 “Gag and Envelope reactivation co-detection assay” (GERDA) enables sensitive detection of Gag+/Env+ protein-expressing cells down to about one cell per million using flow cytometry. By associating GERDA with proviral DNA and polyA-RNA transcripts, we corroborate the presence and functionality of HIV-1 in critical body compartments utilizing t-distributed stochastic neighbor embedding (tSNE) and density-based spatial clustering of applications with noise (DBSCAN) clustering with low viral activity in circulating cells early after diagnosis. We demonstrate transcriptional HIV-1 reactivation at any time, potentially giving rise to intact, infectious particles. With single-cell level resolution, GERDA attributes virus production to lymph-node-homing cells with central memory T cells (TCMs) as main players, critical for HIV-1 reservoir eradication.

Comparison of five different risk scores to predict incident type 2 diabetes in the Swiss HIV cohort study

Abstract: Objective: People with HIV (PWH) have a higher risk of type 2 diabetes (T2D) than HIV-negative individuals. In the general population, diabetes risk scores are used to identify persons at risk of developing T2D, but little is known regarding their performance in PWH. Design: Assessment of the capacity of five diabetes risk scores to predict T2D in PWH. Methods: A prospective study including all Swiss HIV cohort study (SHCS) participants followed between 2009 and 2019. Five diabetes risk scores were assessed: FINDRISC versions 1 and 2, Balkau, Swiss Diabetes Association (SDA), and Kraege. Results: Three thousand eight hundred fifty-three T2D-free PWH (78.5% men, 39.9 ± 11.3 years) were included. After a median follow-up of 4.8 years (interquartile range 2.2–7.8), 62 participants (1.6%) developed T2D, corresponding to an incidence rate of 3.18 per 1000 person-years (95% confidence interval = 2.47–4.08). Participants who developed T2D were older (48.7 ± 12.4 vs. 39.8 ± 11.2 years), more likely to be obese (22.6% vs. 7.4%), abdominally obese (9.7% vs. 1.5%), and to have a family history of diabetes (32.3% vs. 19.1%) than those without T2D. The AUC for incident T2D ranged between 0.72 (Kraege 16) and 0.81 (SDA, FINDRISC2 and Balkau). Sensitivity ranged between 3.2% (Balkau) and 67.7% (FINDRISC1) and specificity between 80.9% (FINDRISC1) and 98.3% (Balkau). Positive predictive values of all scores were below 20%, while negative predictive values were above 98%. Conclusion: Our study shows that the performance of conventional diabetes risk scores in PWH is promising, especially for Balkau and FINDRISC2, which showed good discriminatory power. These scores may help identify patients at a low risk of T2D in whom careful assessment of modifiable T2D risk factors can be spared.

Tenofovir alafenamide and weight: What do we still need to know to inform clinical decisions?

Abstract: BS received travel grants from Gilead Sciences and ViiV Healthcare, and fees for advisory boards from Gilead Sciences, all paid to his institution. GW received unrestricted research grants from Gilead Sciences and Roche Diagnostics, and fees for advisory boards/travel grants from MSD, ViiV Healthcare, and Gilead Sciences, all paid to his institution.

Informing a target product profile for rapid tests to identify HBV-infected pregnant women with high viral loads: a discrete choice experiment with African healthcare workers

Abstract: Elimination of mother-to-child transmission of hepatitis B virus (HBV) requires infant immunoprophylaxis and antiviral prophylaxis for pregnant women with high viral loads. Since real-time polymerase chain reaction (RT-PCR), a gold standard for assessing antiviral eligibility, is neither accessible nor affordable for women living in low-income and middle-income countries (LMICs), rapid diagnostic tests (RDTs) detecting alternative HBV markers may be needed. To inform future development of the target product profile (TPP) for RDTs to identify highly viremic women, we used a discrete choice experiment (DCE) and elicited preference and trade-off of healthcare workers (HCW) in Africa between the following four attributes of fictional RDTs: price, time-to-result, diagnostic sensitivity, and specificity.Through an online questionnaire survey, we asked participants to indicate their preferred test from a set of two RDTs in seven choice tasks with varying levels of the four attributes. We used mixed multinomial logit models to quantify the utility gain or loss generated by each attribute. We attempted to define minimal and optimal criteria for test attributes that can satisfy ≥ 70% and ≥ 90% of HCWs, respectively, as an alternative to RT-PCR.A total of 555 HCWs from 41 African countries participated. Increases in sensitivity and specificity generated significant utility and increases in cost and time-to-result generated significant disutility. The size of the coefficients for the highest attribute levels relative to the reference levels were in the following order: sensitivity (β = 3.749), cost (β = -2.550), specificity (β = 1.134), and time-to-result (β = -0.284). Doctors cared most about test sensitivity, while public health practitioners cared about cost and midwives about time-to-result. For an RDT with 95% specificity, costing 1 US$, and yielding results in 20 min, the minimally acceptable test sensitivity would be 82.5% and the optimally acceptable sensitivity would be 87.5%.African HCWs would prefer an RDT with the following order of priority: higher sensitivity, lower cost, higher specificity, and shorter time-to-result. The development and optimization of RDTs that can meet the criteria are urgently needed to scale up the prevention of HBV mother-to-child transmission in LMICs.

Association of a Polygenic Risk Score with Osteoporosis in People Living with HIV: The Swiss HIV Cohort Study.

Abstract: BACKGROUND Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether an individual polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS We included Swiss HIV Cohort Study participants of self-reported European descent, each with >2 per-protocol Dual X-ray Absorptiometry (DXA) measurements >2 years apart (2011-2020). We obtained uni-/multivariable odds ratios (OR) for DXA-defined osteoporosis based on traditional and HIV-related osteoporosis risk factors and a genome-wide PRS built from 9413 single nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS We included 438 participants (149 with osteoporosis, 289 controls; median age, 53 years, 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis-PRS (top vs. bottom PRS quintile) had univariable and multivariable-adjusted osteoporosis OR=4.76 (95% confidence interval [CI], 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture had univariable osteoporosis-OR=2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9), respectively. CONCLUSIONS In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS, after adjustment for established osteoporosis risk factors including exposure to tenofovir DF.

Hepatitis B in Africa Collaborative Network: cohort profile and analysis of baseline data

Abstract: Abstract Approximately 80 million people live with chronic hepatitis B virus (HBV) infection in the WHO Africa Region. The natural history of HBV infection in this population is poorly characterised, and may differ from patterns observed elsewhere due to differences in prevailing genotypes, environmental exposures, co-infections, and host genetics. Existing research is largely drawn from small, single-centre cohorts, with limited follow-up time. The Hepatitis B in Africa Collaborative Network (HEPSANET) was established in 2022 to harmonise the process of ongoing data collection, analysis, and dissemination from 13 collaborating HBV cohorts in eight African countries. Research priorities for the next 5 years were agreed upon through a modified Delphi survey prior to baseline data analysis being conducted. Baseline data on 4,173 participants with chronic HBV mono-infection were collected, of whom 38.3% were women and the median age was 34 years (interquartile range 28–42). In total, 81.3% of cases were identified through testing of asymptomatic individuals. HBeAg-positivity was seen in 9.6% of participants. Follow-up of HEPSANET participants will generate evidence to improve the diagnosis and management of HBV in this region.