2019

2nd May Kusejko et al., Interaction of HIV-1 with comorbidities


A systematic phylogenetic approach to study the interaction of HIV-1 with coinfections, non-communicable and opportunistic diseases.    Journal of Infectious Disease

Kusejko et al. aimed to systematically test whether coinfections spread along the HIV-1 transmission network and whether similarities in HIV-1 genomes predict AIDS-defining illnesses and comorbidities.

A maximum-likelihood phylogenetic tree was built using sequences of 11’915 patients from the genotypic resistance test database of the Swiss HIV Cohort Study (SHCS) and non-Swiss background sequences from the Los Alamos database.

Among the coinfections, hepatitis C virus (HCV), hepatitis B virus (HBV), syphilis, cytomegalovirus CMV, and latent tuberculosis all clustered significantly on the tree, even after adjusting for risk factors. Several opportunistic diseases such as Kaposi sarcoma clustered significantly on the phylogeny. For most noncommunicable diseases analyzed, patients were likewise not distributed randomly on the phylogeny. In most cases, however, the clustering was not significant in the multivariable analysis. Clustering of patients with psychiatric problems and neurocognitive complaints became weaker in the multivariable mixed effects model, but the odds of having psychiatric problems and neurocognitive complaints if the other patient in the cherry had these problems remained significantly increased.

In conclusion, this work for the first time presents a systematic analysis of interrogating the HIV phylogeny at a population level for the syndemic nature of coinfections and noncommunicable diseases for virus traits potentially relevant for certain diseases. The large variety of conditions tested implies that no universal explanation or interpretation of the clustering can be given. There is evidence for 3 different reasons for clustering: shared transmission routes of pathogens, similar social networks of patients close in the phylogeny, and direct viral genetic impact. Overall, the strategy proposed by the authors together with adjustment for numerous known confounding factors, demonstrates the potential for a new type of analysis, extending conventional epidemiological analyses.

PubMed

23rd April obituary Dr. Joseph Jost

Dear all,

It is with great sadness that I inform you of the passing of our dear colleague Dr. Joseph "Seppi" Jost. He died suddenly and unexpectedly during the ECCMID meeting in Amsterdam last week. Seppi was a highly talented and dedicated ID physician, a pioneer of HIV medicine in Switzerland and instrumental in setting up the Swiss HIV Cohort Study.

He worked at the Division of Infectious Diseases and Hospital Epidemiology of the University of Zurich as an "Oberarzt" from 1986-1999. In 1999, he went into private practice in Zurich and continued to care for hundreds of patients living with HIV.

Seppi was a member of the KOHEX physicians (physicians participating in the Swiss HIV Cohort Study in Zurich) and remained always a highly motivated partner of the SHCS.

On behalf of the SHCS, I want to thank Seppi for all the great work he has done for his patients and for his commitment to the SHCS. On a personal note, I want to thank him for all I was able to learn from him during my ID fellowship at the USZ in 1991-1993. Seppi was not only a great physician but had also a great sense of humor and it was always true fun to work with him.

Seppi will be truly missed. Our deepest sympathies go to his wife and two children.

for the SHCS,
Huldrych Günthard
President of the SHCS

17th April Salazar-Vizcaya et al., International versus local HCV transmission


Changing trends in international versus domestic HCV transmission in HIV-positive MSM: A perspective for the DAA scale-up era.    Journal of Infectious Disease

Salazar-Vizcaya et al. aimed to classify hepatitis C virus (HCV) infections in HIV-positive men who have sex with men (MSM) in Switzerland as domestically or internationally acquired, and to estimate how this classification changed over time.

The authors sequenced HCV subtype 1a genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections. Sixty-six of these sequences were from MSM. They inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. They inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission.

Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0%–75%). It increased to 85% (range 67%–100%) between 2008 and 2016. The authors found no significant trace of transmission bridging from persons who became infected with HIV through drug injection and MSM within Switzerland, suggesting that the HCV epidemics in these 2 HIV transmission groups are likely disconnected.

In conclusion, this molecular epidemiological study suggests that both international and local transmission have played major roles in the Swiss epidemic of HCV among HIV-positive MSM, and that, while international transmission persists, Swiss domestic transmission has gained importance over time.

PubMed

10th April Wymant et al., Reconstruction of whole HIV genomes from short-read sequence


Easy and accurate reconstruction of whole HIV genomes from short-read sequence data with SHIVER.   Virus Evolution

Studying the evolution of viruses and their molecular epidemiology relies on accurate viral sequence data, so that small differences between similar viruses can be meaningfully interpreted. Despite its higher throughput and more detailed minority variant data, next-generation sequencing has yet to be widely adopted for HIV. The difficulty of accurately reconstructing the consensus sequence of a quasispecies from reads (short fragments of DNA) in the presence of large between and within-host diversity may have presented a barrier. In particular, mapping (aligning) reads to a reference sequence leads to biased loss of information; this bias can distort epidemiological and evolutionary conclusions. De novo assembly avoids this bias by aligning the reads to themselves, producing a set of sequences called contigs. However, contigs provide only a partial summary of the reads, misassembly may result in their having an incorrect structure, and no information is available at parts of the genome where contigs could not be assembled.

To address these problems, Wymant and colleagues on behalf of the BEEHIVE collaboration developed the tool shiver to pre-process reads for quality and contamination, then map them to a reference tailored to the sample using corrected contigs supplemented with the user’s choice of existing reference sequences. Run with two commands per sample, it can easily be used for large heterogeneous data sets. The authors used shiver to reconstruct the consensus sequence and minority variant information from paired-end short-read whole-genome data produced with the Illumina platform, for sixty-five existing publicly available samples and fifty new samples. They showed the systematic superiority of mapping to shiver’s constructed reference compared with mapping the same reads to the closest of 3,249 real references: median values of 13 bases called differently and more accurately, 0 bases called differently and less accurately, and 205 bases of missing sequence recovered. They also successfully applied shiver to whole-genome samples of Hepatitis C Virus and Respiratory Syncytial Virus.

In conclusion, the authors developed the tool shiver to preprocess and map reads from each sample to a custom reference, constructed using de novo assembled contigs supplemented by existing reference genomes. Tailoring the reference to be as close as possible to the expected consensus before mapping maximizes the accuracy of the mapping, and therefore of the resulting consensus. Shiver’s identification, ranking, and use of the closest existing references to fill in gaps between contigs boosts data recovery for samples with amplification failure or assembly failure. In addition, shiver also produces a global alignment containing all of the consensuses separately generated for each sample, which is usually required for comparative analysis of the sequences such as for phylogenetics or genome wide association studies. Shiver is publicly available from https://github.com/ChrisHIV/shiver

pdf publication

4th April Wymant et al., Inferring transmission from within- and between-host pathogen genetic diversity


PHYLOSCANNER: Inferring Transmission from Within- and Between-Host Pathogen Genetic Diversity.   Molecular Biology and Evolution

A central feature of pathogen genomics is that different infectious particles (virions and bacterial cells) within an infected individual may be genetically distinct, with patterns of relatedness among infectious particles being the result of both within-host evolution and transmission from one host to the next.

In the current work, Wymant and colleagues on behalf of the BEEHIVE Collaboration present a new software tool, phyloscanner, which analyses pathogen diversity from multiple infected hosts. The show that phyloscanner provides unprecedented resolution into the transmission process, allowing inference of the direction of transmission from sequence data alone. In addition, phyloscanner allows to identify multiply infected individuals, as they harbor subpopulations of infectious particles that are not connected by within-host evolution, except where recombinant types emerge. Low-level contamination is flagged and removed.

The authors illustrate phyloscanner on both viral and bacterial pathogens, namely HIV-1 sequenced on Illumina and Roche 454 platforms, Hepatitis C virus sequenced with the Oxford Nanopore MinION platform, and Streptococcus pneumoniae with sequences from multiple colonies per individual.

In conclusion, phyloscanner aims to simplify identification of transmission, multiple infection, recombination, and contamination across pathogen genomics by providing a tool for automatic phylogenetic analysis of next generation sequencing deep sequencing data, or multiple genotypes per host generated by other means. Phyloscanner is available from https://github.com/BDI-pathogens/phyloscanner.

pdf publication

28th March Peters et al., Uptake of TDF-based ART among HIV/HBV co-infected patients


Uptake of tenofovir-based antiretroviral therapy among HIV/HBV co-infected patients in the EuroSIDA study.    Antiviral Therapy

Peters et al. on behalf of the EuroSIDA study aimed to study regional differences in uptake of tenofovir disoproxil fumarate (TDF-) based combination antiretroviral therapy (cART) and factors associated with its use among HIV/hepatitis B virus (HBV) co-infected patients across Europe.

Overall, 953 HBsAg+ patients were followed up after 1 March 2002. Median age was 41 years and patients were predominantly male (85%), white (82%) and ART experienced (88%). 697 and 256 were from Western and Eastern Europe, respectively. Fifty-five started cART during follow-up, the proportion starting with CD4

  • TDF use, among those taking cART, increased from 4% in 2002 to 73% in 2015.
  • Compared to West, TDF use was lower in East in 2005 (7% vs. 42%), and remained lower in 2015 (63% vs. 76%).
  • Among 602 patients taking TDF-based cART during follow-up. 155 (26%) discontinued TDF.
  • Twenty-seven (17%) of all TDF discontinuations were due to adverse events.
  • Only 14 started entecavir and/or adefovir after TDF discontinuation, whereas ten started PEG-IFN.
  • TDF use was not significantly associated with lower risk of liver-related clinical events (N=51), adjusted IRR 0.64 (95% CI 0.35-1.18) for comparing patients on TDF with those off TDF.

In conclusion, in this large pan-European observational study we have shown a large proportion of HIV/HBV co-infected patients have started cART late and seem to receive sub-optimal coverage against HBV, in particular in Eastern Europe. Discontinuations of TDF without replacement with antiviral agents with sufficient antiviral coverage against HBV are common, and put the patients at risk of hepatic flares and progression of liver disease. Longer follow-up is warranted to investigate whether treatment with less potent HBV active antivirals translates into greater risk of clinical liver disease and death among HIV/HBV co-infected patients.

PubMed

20th March Gran et al., Estimating treatment effect under time-dependent confounding


Estimating the treatment effect on the treated under time-dependent confounding in an application to the Swiss HIV Cohort Study.   Journal of the Royal Statistical Society

When comparing time varying treatments in a non-randomized setting, one must often correct for time-dependent confounders that influence treatment choice over time and that are themselves influenced by treatment.

In the current work, Gran and colleagues present a new two-step procedure, based on additive hazard regression and linear increments models, for handling such confounding when estimating average treatment effects on the treated. The approach can also be used for mediation analysis.

The method is applied to data from the Swiss HIV Cohort Study, estimating the effect of antiretroviral treatment on time to acquired immune deficiency syndrome or death. Compared with other methods for estimating the average treatment effects on the treated the method proposed is easy to implement by using available software packages in R.

In sum, compared with other methods that estimate average total treatment effect under time-dependent confounding on a time-to-event outcome, the proposed method is a two-step approach, where each step has the benefit of being easy to implement by using two simple existing statistical software packages.

The outcome model also has the benefit of being a hazard regression model in the traditional sense, which typically is not so in the g-estimation approach. The authors claim that there are advantages in considering several approaches for handling the thorny issue of time-dependent confounding, and that the procedure that is described in this paper serves as a valuable addition.

pdf publication

14th March Shepherd et al., Risk factors for Non-Hodgkin and Hodgkin lymphoma


Differences in virological and immunological risk factors for Non-Hodgkin and Hodgkin lymphoma.   Journal of the National Cancer Institution.

Shepherd et al. on behalf of the Data Collection on Adverse events Cohort (D:A:D) aimed to identify independent risk factors of Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) and to identify factors that differentially affect NHL and HL risk in order to develop an understanding of different mechanistic pathways, which may then suggest different preventive approaches for reducing NHL and HL risk.

  • Among 41’420 people followed for 337’020 person-year, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] =1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI=0.38 to 0.52).
  • Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs>599 cells/mm3 = 8.08, 95% CI=5.63 to 11.61; HL=4.58, 95% CI=2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs<50 copies/mL = 1.97, 95% CI=1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI=1.92 to 4.41) were associated with NHL only.
  • Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL.

In conclusion, the study shows that whereas CD4 depletion similarly increased risk of both types of lymphomas, current and accumulated HIVVL was more predictive of NHL than HL. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk. These findings stress the importance of early HIV diagnosis and treatment, and of ensuring sustained viral suppression.

PubMed

28th February Laut et al., Disparities in ART coverage and virological suppression across Europe


Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.    Eurosurveillance

Laut et al. on behalf of the EuroSIDA Study Group aimed to characterize country-specific levels of antiretroviral therapy (ART) coverage and ART-induced HIV RNA suppression (HIV RNA < 500 copies/mL) within the EuroSIDA study, and to monitor temporal trends. Of note, the cut-off of 500 copies/mL for viral suppression was chosen as not all countries have access to assays with a lower limit of detection of 50 copies/mL

Overall, the percentage of people on ART increased from 2004–05 (67.8%) to 2014–15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004–05, 87.7% in 2014–15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014–15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe, patients in other regions were less likely to be virologically suppressed in 2014–15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13–0.21) in Eastern Europe.

In conclusion, the study was able to directly compare data from a large number of clinics across Europe, including some countries that do not have national registries. The authors found persistent between-country disparities in the level of ART coverage and virological suppression, as well as the rate of improvement over the last decade. EuroSIDA will continue the surveillance of changes and variation in countries’ performance in the ‘test and treat’ era. Current EuroSIDA work aims to explore the underlying reasons for the observed variation, with the goal to identify a best practice and to benchmark HIV care.

pdf publication

21st February Huges et al., Trends in CD4+:CD8+ ratio on ART


Long-term trends in CD4 cell counts, CD8 cell counts, and the CD4: CD8 ratio: ART Cohort Collaboration (ART-CC) Study.   AIDS

HIV infection leads to persistent immune activation and inflammation, which may accelerate deterioration of the immune system due to ageing (so called “immunosenescence”). In the general population, a low CD4+:CD8+ ratio is a surrogate marker for immunosenescence and an independent predictor of all-cause mortality. Among HIV-positive individuals, low CD4+:CD8+ ratio has been associated with higher levels of immunosenescence and inflammation, although the results regarding whether a low or inverted CD4+:CD8+ ratio predicts non-AIDS-related morbidity and mortality have been conflicting.

In the current work, Hughes et al. on behalf of the ART Cohort Collaboration aimed to quantify long-term trends in CD8+ cell counts and CD4+:CD8+ ratios, up to 15 years after starting antiretroviral therapy (ART), in a large cohort of antiretroviral-naïve individuals starting ART, and assess the impact of baseline CD4+ cell count on these trends.

Eligible patients from the ART Cohort Collaboration were antiretroviral-naïve, started ART after 1997, had at least one CD4+ and CD8+ measurement within the baseline period and one or moreCD4+ and CD8+ measurements 6 months after starting ART.

A total of 39’979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/ml, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+:CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+:CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/ml. A higher baseline CD4+ cell count predicted a shorter time to normalization.

In conclusion, there are long-term decreases in CD8+ cell counts and long-term increases in CD4+:CD8+ ratios, among patients who start ART with CD4+ cell count as low as 50–199 cells/ml. However, starting ART at high CD4+ cell counts is paramount for attainment of a maximal CD4+:CD8+ ratio.

PubMed

20th February Kurioka et al., CD161-expressing NK cells


CD161 defines a functionally distinct subset of pro-inflammatory NK cells.    Frontiers

Natural killer (NK) cells are the most classical population of innate lymphoid cells, expressing a heterogeneous repertoire of germline-encoded receptors that allows them to distinguish infected or stressed cells from healthy cells. CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, the author-group has found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations.

In the current work, Kurioka et al. demonstrated using mass cytometry and microarray experiment that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression.

In summary, the study has shown that CD161 is a marker of NK cell function, particularly marking pro-inflammatory NK cells, which is expressed on all NK cells in cord blood, downregulated upon proliferation, and lost upon CMV-induced terminal differentiation. CD161 expression on CD56dim NK cells marks cells that have retained the capacity to respond to inflammatory cytokines alone. CD161, thus, identifies “innate” cells within both NK cells and CD161bright T cell family, previously described, with shared innate-type responses that are independent of receptorligation.

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13th February Laut et al., Variation among HIV key populations


Variation in antiretroviral treatment (ART) coverage and virological suppression among three HIV key populations.   AIDS

Laut et al. on behalf of the EuroSIDA study group aimed to assess differences in antiretroviral treatment (ART) coverage and virological suppression across the three HIV transmission categories i) men who have sex with men, ii) injection drug users (IDU) and iii) heterosexuals.

Among 12’872 participants followed from 1 July 2014 to 30 June 2016, the percentages of ART-coverage and virological suppression varied between transmission categories, depending on geographical region (global P for interaction: P=0.0148 for ART-coverage, P=0.0006 for virological suppression).

• In Western [adjusted odds ratio (aOR) 1.41 (95% confidence interval 1.14–1.75)] and Northern Europe [aOR 1.68 (95% confidence interval 1.25–2.26)], heterosexuals were more likely to receive ART than MSM.

• In Eastern Europe, there was some evidence that infection through IDU [aOR 0.60 (95% confidence interval 0.31–1.14)] or heterosexual contact [aOR 0.58 (95% confidence interval 0.30–1.10)] was associated with lower odds of receiving ART.

• In terms of virological suppression, people infected through IDU or heterosexual contact in East Central and Eastern Europe were around half as likely as MSM to have a suppressed viral load on ART.

• There were no differences in virological suppression observed across transmission categories in Western and Northern Europe.

In conclusion, the study found that levels of ART-coverage and virological suppression varied depending on HIV transmission category, both across and within regions. Overall, people infected through IDU were the least likely to receive ART and to achieve virological suppression on ART, but the pattern varied significantly by region of residence. These results demonstrate that national estimates of ART coverage and virological suppression may represent an average that covers large differences across key populations. Hence, a differentiated HIV-response remains crucial to reaching control of the HIV epidemic and underline that high-quality disaggregated data are needed to inform and strengthen interventions.

PubMed

6th February Rohner et al, Regional NHL risk in HIV-positive adults


Non-Hodgkin lymphoma risk in adults living with HIV across five continents.    AIDS

Rohner et al. for the AIDS-defining Cancer Project Working Group of IeDEA and COHERE in EuroCoord aimed to compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) after 1995 across the Asia-Pacific, South Africa, Europe, Latin, and North America.

The authors included 210’898 adults with 1.1 million person-years (pys) of follow-up and 1’552 incident NHL cases (raw overall incidence rate 142/100 000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4+ cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts [adjusted hazard ratio [aHR] 1.79, 95% CI 1.19–2.70]. In Europe, Latin, and North America, NHL risk was highest in MSM (aHR 1.30, 95% CI 1.14–1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57–0.78).

In conclusion, the risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Co-infection patterns might contribute to the increased NHL rates in MSM and South African women. A better understanding of lymphomagenesis and associated etiologic factors is needed to eventually be able to develop specific preventive measures against NHL in adults living with HIV. In the meantime, early access to ART and regular patient monitoring to avert low current CD4+ cell counts remain key for NHL prevention.

PubMed

30th January Ronit et al., Serum albumin and non-AIDS events


Associations between serum albumin and serious non-AIDS events among people living with HIV.   AIDS

Ronit et al. for the D:A:D Study Group aimed to undertake a detailed evaluation of the association between serum albumin (sAlb) and serious non-AIDS events (SNAE) in a large and heterogeneous study population with long follow-up.

SNAE was defined as cardiovascular disease (CVD) (myocardial infarction, stroke, invasive cardiovascular procedure or death from CVD); end-stage renal disease (ESRD) or death from renal disease; end-stage liver disease (ESLD) or death from ESLD; non-AIDS-defining malignancies (NADMs, except for basal cell or squamous cell skin cancer) or death from cancer; and any other non-AIDS death.

Of 16’350 participants (71.8% male, median age 44 years), 1’463 developed an SNAE (371 CVD, 200 ESLD, 40 ESRD, 553 NADM, 299 deaths from other non-AIDS causes) over 80’264 person-years. Increased sAlb was associated with a decreased risk of an SNAE [adjusted rate ratio per 5 g/l: SNAE 0.79 (95% confidence interval: 0.76, 0.83); CVD 0.87 (0.80, 0.94); NADM 0.88 (0.82, 0.95)]. The association did not appear to wane with additional years of follow-up (P-interaction =0.79) but was stronger for current smokers than for never smokers (P-interaction <0.01).

In conclusion, in this study sAlb was found to be independently associated with SNAE, including CVD and NADM. This association did not appear to wane over time and was strongest in current smokers. The pathophysiology underlying the relationship between sAlb and SNAE, and its effect modifiers, are poorly understood, and warrants further mechanistic investigation. One potential explanation is that a low sAlb level might be a consequence of pathways of immune activation and that sAlb may exert a protective effect due to antioxidant activity.

PubMed

29th January Shepherd et al., Cessation of cigarette smoking and cancer in HIV


Cessation of cigarette smoking and the impact on cancer incidence in HIV-positive persons: The D:A:D Study.     Clinical Infectious Diseases

Despite the well characterized harms of smoking in people living with HIV (PLWH), the clinical benefits of smoking cessation on cancer risk have not previously been reported in large epidemiological studies. The aim of this study was to estimate cancer rates after smoking cessation in PLWH from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.

Participants were followed from 1 January 2004 until first cancer diagnosis, death, or 1 February 2016. Smoking status was defined as ex-smoker, current smoker, and never smoker. Of note, smoking information is reported in the D:A:D Study as current smoker (yes/no) and ever smoker (yes/no) at each visit, but more specific information, such as cigarette or pipe smoking, or intensity of smoking, is not available.

In total 35’442 persons from the D:A:D study contributed 309’803 person-years of follow-up. At baseline, 49% were current smokers, 21% were ex-smokers, and 30% had never smoked.

• Incidence of all cancers combined (n = 2’183) was highest <1 year after smoking cessation compared to never smokers (aIRR, 1.66 [95% confidence interval {CI}, 1.37–2.02]) and not significantly different from never smokers 1–1.9 years after cessation.

• Lung cancer incidence (n = 271) was elevated <1 year after cessation (aIRR, 19.08 [95% CI, 8.10–44.95]) and remained 8-fold higher 5 years after smoking cessation (aIRR, 8.69 [95% CI, 3.40–22.18]). 

• Incidence of other smoking-related cancers (n = 622) was elevated in the first year after cessation (aIRR, 2.06 [95% CI, 1.42–2.99]) and declined to a level similar to nonsmokers thereafter.

In conclusion, incidence of lung cancer incidence in PLWH was >8-fold higher than never smokers several years after cessation, at a similar level to current smokers, and with no evidence of a decline after the first year. This suggests that the oncogenic potential for smoking is not reduced for lung cancer in the time frame that was investigated. This is in contrast with similar studies in HIV-uninfected people, which show a consistent decline in lung cancer incidence with increasing time since cessation. Deterring uptake of smoking and smoking cessation efforts should be a priority to reduce the risk of cancer; however, monitoring and awareness of lung cancer should continue in those who stop smoking. Studies following PLWH throughout their lifetimes are needed to determine when the benefit of cessation will be seen.

PubMed

23rd January Slogrove et al., The epidemiology of adolescents living with perinatally acquired HIV


The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.   PLoS Medicine

Slogrove et al. for the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration aimed to describe the global epidemiology of adolescents living with perinatally acquired HIV (APH) in terms of geographic and temporal trends of patient and treatment characteristics at entry into care, ART start, entry into adolescence (age 10 years), and last visit.

All children from 12 cohort networks infected with HIV who entered care before age 10 years and had acquired HIV around the time of birth or through breastfeeding, were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017.

Among 38’000 adolescents living with perinatally acquired HIV, 79% were living in sub-Saharan Africa. Analysis by country income group suggested that patients in high-income countries (North America and Europe) had younger age, higher CD4 percent, and less impaired height when starting antiretroviral therapy compared to middle- or low-income countries. Lost to follow-up rate was lowest in South America and the Caribbean and highest in sub-Saharan Africa. HIV-associated mortality during adolescence was substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe.

In summary, the analysis of a large cohort of APHs between 1982 and 2014 across several regions of the globe suggests that APHs generally entered HIV care at an earlier age in high-income countries compared to other country income groups. Despite probable under-ascertainment, mortality continued to be substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe and warrants further monitoring and understanding.

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17th January Ramsuran et al., Inhibiting natural killer cells in AIDS


Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.   Science

The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference.

Ramsuran et al. examined data from 9’763 HIV-infected individuals from 21 cohorts. They found that higher HLA-A levels confer poorer control of HIV.

Expression of the HLA-A and -B alleles was associated with:
    - higher viral load
    - reduced CD4+ T cell counts
    - accelerated progression to AIDS.

Higher levels of HLA-A expression increased expression of HLA-E, which blocks a specific receptor (NKG2A) on the immune cells that normally eliminate virus-infected cells.

In conclusion, the data suggest that antagonizing HLA-E/NKG2A interactions, perhaps in combination with other therapies, may provide benefit in HIV disease. This might be an attractive approach in HIV cure strategies. Genetic validation of NKG2A as a therapeutic target in additional diseases by testing for effects of HLA-A and HLA-B –21 genotypes may rationalize the use of anti-NKG2A therapy in other disorders.

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16th January Pelchen-Matthews et al., Comorbidities in people living with HIV


Aging and the evolution of comorbidities among HIV-positive individuals in a European cohort.    AIDS

Pelchen-Matthews et al. for the EuroSIDA study aimed to characterize the evolution of the prevalence of chronic kidney disease (CKD) and cardio-vascular disease (CVD) and related risk factors in the aging people living with HIV (PLWHIV) population in Europe.

9’798 individuals were under active follow-up in EuroSIDA during 2006 and 12’882 during 2014.

Compared with study participants in 2006, those in 2014:
- were older [median age 48.6 years (IQR 40.3–55.1) vs. 43.1 years (37.2–50.0) in 2006]

- had higher prevalence of
   o hypertension (59.6 vs. 47% in 2006),
   o diabetes (6.3 vs. 5.4%),
   o CKD (6.9 vs. 4.1%)
   o CVD (5.0 vs. 3.7%).

Individuals in the 2014 cohort had higher odds for CKD (unadjusted OR 2.62, 95% CI2.30–2.99, P<0.0001) and CVD (OR 1.88, CI 1.68– 2.10, P<0.0001), but after multivariable adjustment for age group, comorbidities and other factors, year of cohort was no longer significantly associated with the odds of CKD [adjusted OR (aOR) 0.97, CI 0.52– 1.82, P=0.92) or of CVD (aOR 0.94, CI 0.54 –1.63, P=0.82).

In conclusion, this study of risk factors and comorbidities in a large cohort of HIV-positive individuals in Europe has shown an increase in the prevalence of non-AIDS comorbidities, including diabetes, CKD and CVD, along with increased prevalence of hypertension and a high prevalence dyslipidemia, which was largely explained by the aging of persons included. Higher prevalence of comorbidities was particularly evident for individuals at least 50 years old, highlighting the increase in non-AIDS-related conditions in the aging PLWHIV population. This shows a need for careful management not only to control HIV through optimal selection of ART, but also to address the effect of aging, including screening and regular monitoring of the major comorbidities and risk modification measures.

PubMed