24th May Efsen et al., Management of HIV-positive patients with MDR-TB in Eastern Europe

Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study.    Journal of Infection

Efsen et al. on behalf of the TB: HIV study in EuroCoord aimed to describe the tuberculosis (TB) treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART) in Eastern Europe. MDR-TB was defined as TB resistant to rifampicin and isoniazid, whereas extensively drug-resistant tuberculosis (XDR-TB) had additional resistance against a fluoroquinolone and a second-line injectable drug.

Overall, 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95% CI 41.5– 74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%.

In conclusion, the study shows that in Eastern Europe there is an urgent need for access to rapid diagnostics to guide initial TB treatment, to extend susceptibility testing to all patients diagnosed with rifamycin-resistant or MDR-TB and to provide better access to second line drugs to allow the administration of optimally active MDR-TB regimens. Integration of TB and HIV services can ensure better management and support for people with HIV who frequently have IDU and hepatitis C virus coinfection, including rapid initiation of fully suppressive ART.


23rd May Dolutegravir containing ART regimens in HIV-1-infected pregnant women and their infants

Efficacy and safety of dolutegravir containing ART regimens in HIV-1-infected pregnant women and their infants

Due to actual reasons, the press release of this week summarizes the latest news of the IMPACT 2010 study, investigating the efficacy and safety of dolutegravir containing antiretroviral therapy in pregnant women. So far, productive toxicology studies and other data on the use of dolutegravir in pregnancy, including data from the Antiretroviral Pregnancy Registry (APR), clinical trials and post-marketing use did not indicate a risk of neural tube defects.

The IMPACT 2010 study was launched by the National Institute of Healthy, is a phase 3 study, and aimed to enroll 639 women who are 14 to 18 weeks pregnant, are living with HIV, and are not currently taking antiretroviral treatment. The women were randomly assigned to be administered efavirenz/emtricitabine/tenofovir fumarate disoproxil (EFV/FTC/TDF), dolutegravir/FTC/tenofovir alafenamid fumarate (DTG/FTC/TAF), or DTG/FTC/TDF. Their infants were also enrolled in the study and received local standard-of-care interventions for HIV prophylaxis following birth. Both the women and their infants were followed for 50 weeks after delivery. Participating clinical trial sites included the United States, Zimbabwe, Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania, Thailand, and Uganda. The final results of the study are expected in about a year.

So far, the study looked at babies born to 11’558 HIV-infected women in Botswana and showed that 0.9% of babies (4 of 426) whose mothers became pregnant while taking dolutegravir had a neural tube defect, compared with 0.1% of babies (14 of 11’173) whose mothers took other HIV medicines. No cases were reported in infants born to women who started dolutegravir later during pregnancy.

In conclusion, this preliminary data suggest that the potential safety issue arises from a woman’s exposure to dolutegravir at the time of conception, rather than during pregnancy. Currently, there is no evidence of any infant born with a neural tube defect to a woman who started dolutegravir during her pregnancy. As a precaution, healthcare are advised of the following:

  • Do not prescribe dolutegravir for women of childbearing potential who are trying to become pregnant.
  • Exclude pregnancy in women of childbearing potential before starting dolutegravir.
  • Advise women of childbearing potential who are taking dolutegravir to use effective contraception throughout treatment
  • If pregnancy is confirmed in the first trimester while a woman is taking dolutegravir, switch to an alternative treatment unless there is no suitable alternative

Comment Dr. Dominique Braun and Prof. Huldrych Günthard, SHCS
As a direct consequence from this preliminary results, HIV post-exposure prophylaxis (PEP) with dolutegravir should not be prescribed to women of childbearing potential unless a pregnancy has been ruled out before starting PEP. With regard to the consequences for the Simpl’HIV study, the sponsor team in Geneva is currently preparing an information letter that will distributed soon.


17th May Santos et al., Effectiveness of boosted PI-based therapy in Europe

Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe.    HIV Medicine

Santos et al. on behalf of the EuroSIDA study group aimed to evaluate the long-term effectiveness of different protease inhibitor (PI) containing regimens initiated at various stages during participants’ antiretroviral therapy (ART) history and the factors associated with virological failure (VF), treatment discontinuation, and CD4 cell count recovery in a large European cohort of HIV-1-infected patients. Data were analysed for 5’678 EuroSIDA-enrolled patients starting a darunavir/ritonavir (DRV/r)-, atazanavir/ritonavir (ATZ/r)- or lopinavir/ritonavir (LPV/r)-containing regimen between 1 January 2000 and 30 June 2013. VF was defined as two consecutive viral load measurements >200 copies/mL ≥24 weeks after PI/r initiation.

Of these 5678 patients, a total of 431 (8%) were ART-naïve patients of whom 220 (51%) were receiving LPV/r, 119 (28%) were on ATZ/r, and 92 (21%) were on DRV/r-based regimens. The median (IQR) time of follow-up was 28 (11–57) months. The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. Injecting drug use, higher HIV-1 RNA at baseline, black ethnicity, having historic genotyping tests available, and a higher number of prior failures on non-PI-based ART were independent predictors of an increased hazard of VF. The risk of PI/r discontinuation for any reason was > 2.5 times higher in patients who started LPV/r-based ART than in those initiating a DRV/r-based ART, while no significant difference was observed when ATZ/r and DRV/r regimens were compared.

In summary, assuming no unmeasured confounding factors, the long-term effectiveness of boosted PI-containing regimens in ART-experienced subjects appears to be greater in people receiving DRV/r than in those receiving ATZ/r and LPV/r. The same tendency was observed in ART-naïve patients, although the analysis was likely to be underpowered in this population. Strategies to improve clinical care and treatment response continue to be necessary in some subsets of the HIV-infected population such as women, injecting drug users, hepatitis virus-coinfected patients and ethnic minorities.


16th May Raisaro et al., Privacy-enhancing technologies for genomic data

Are privacy-enhancing technologies for genomic data ready for the clinic? A survey of medical experts of the Swiss HIV Cohort Study.    Journal of Biomedical Informatics

Raisaro et al. aimed to describe end-users’ perception of genome privacy and their attitude toward the use of sophisticated PETs in an operational clinical setting.

The participating physicians had access to the system for privacy-preserving genetic testing through a Java front-end application installed at each of the participating SHCS hospitals. The application included a graphical user interface enabling physicians to select patients using a unique identifier and the genetic tests to be performed on the patient’s encrypted genotype. The request was then sent to the system back-end deployed at the Data Center in Lausanne. Patients’ genomic data were never decrypted and the encrypted test results were returned to the local front-end for decryption. A standardized text report indicated an increased or decreased risk of the tested trait due to genetic factors, or a result of “no relevant alleles found” was presented to the physician. After using the system, the physicians were asked to answer an electronic survey directly embedded in the front-end application.

Overall, 38 out of 55 (69%) physicians participated in the study. Two thirds of them acknowledged genetic privacy as a key aspect that needs to be protected to help building patient trust and deploy new-generation medical information systems. All of them successfully used the tool for evaluating their patients’ pharmacogenomics risk and 90% were happy with the user experience and the efficiency of the tool. Only 8% of physicians were unsatisfied with the level of information and wanted to have access to the patient’s actual DNA sequence.

In conclusion, this survey represents the first evaluation of privacy-preserving models for genomic-based medicine. In particular, the study-results show that a clinical information system that uses homomorphic encryption to provide clinicians with risk information based on sensitive genetic test results can offer information that clinicians feel sufficient for their needs and appropriately respectful of patients’ privacy. The study presented here derives unique insights that maybe will guide the design and facilitate the adoption of these systems in the future, by better addressing physicians’ requirements.


9th May Anderegg et al., Immunodeficiency at cART Initiation

Global trends in CD4 cell count at the start of antiretroviral therapy: Collaborative Study of Treatment Programs.    Clinical Infectious Disease

Anderegg et al. on behalf of IeDEA and COHERE examined global trends in CD4 cell counts at combination antiretroviral therapy (cART) initiation among adults from low-income (LICs), lower-middle-income (LMICs), upper-middle-income (UMICs), and high-income (HICs) countries.

A total of 951’855 adults were included. Overall, the modeled median CD4 cell count at the start of cART increased from 2002 to 2015,

from 78/μL to 287/μL in LICs,
from 99/μL to 234/μL in LMICs,
from 71/μL to 311/μL in UMICs, and
from 161/μL to 327/μL in HICs.

In LICs, LMICs, and UMICs, the increase was more pronounced in women; in HICs, the opposite was observed. There were important differences between regions: the estimated median CD4 cell count in 2014 among individuals starting cART in North America rose to 435/μL in 2014; at the other end of the spectrum, it was 186/μL in individuals starting cART in West Africa in the same year. In LICs, the estimated proportion of adults starting with severe immunodeficiency (= CD4 cell count <200/μL) declined from 95% in 2002 to 31% in 2015. Corresponding declines were from 75% to 40% in LMICs, from 79% to 26% in UMICs, and from 59% to 29% in HICs.

In conclusion, the study-results show that median CD4 cell counts at the start of cART have increased in all country income groups over the last few years, and the proportion of individuals starting cART with severe immunodeficiency has decreased. However, the median CD4 cell count at cART start generally remained below 350/μL in 2015 and the decline in severe immunodeficiency appears to have plateaued in some countries. Clearly, substantial additional efforts and resources will be needed to achieve early diagnosis, rapid linkage to care, and prompt initiation of cART globally.

pdf publication

25th April Young et al., Pill count and clinical outcome in HIV

Antiretroviral pill count and clinical outcomes in treatment-naïve patients with HIV infection.    HIV Medicine

Young et al. assessed whether the one-pill combination of efavirenz, emtricitabine and tenofovir reduces the risk of AIDS or death in treatment-naïve HIV-infected patients starting ART compared with two- or three-pill formulations of the same regimen. The analysis was based on data from the Antiretroviral Therapy Cohort Collaboration (ART-CC) of observational HIV-infected cohorts from Europe and Northern America to predict the potential consequences of exposing a future population to either a one-pill regimen or a three-pill regimen.

Among 11’739 treatment-naïve patients starting the regimen, there were 386 AIDS events and 87 deaths. Follow-up often ended when patients switched to the same regimen with fewer pills. After the first month, two pills rather than one was associated with an increase in the risk of AIDS or death [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.01-1.91], but three pills rather than two did not appreciably add to that increase (HR 1.19; 95% CI 0.84-1.68). The authors estimated that 77 patients would need to be exposed to a one-pill regimen rather than a three-pill regimen for 1 year to avoid one additional AIDS event or death.

In conclusion, the study-results show that the one-pill combination of efavirenz, emtricitabine and tenofovir was associated with a modest decrease in the risk of progression to AIDS or death compared with two- or three-pill formulations of the same regimen. However, the authors conclude that this does not imply that a single tablet regimen should be used rather than a multiple-pill formulation of the same regimen using generic drugs. Rather, the authors provided statistics that could be used to evaluate whether single tablet regimen are more cost-effective than other formulations.


19th April Strouvelle, Braun et al., Effect of pIFN-α on total HIV-1 DNA load

No effect of pegylated interferon-alpha on total HIV-1 DNA load in HIV-1/HCV coinfected patients.    Journal of Infectious Diseases

Strouvelle, Braun et al. aimed to examine the effect of pegylated interferon-alpha (pIFN-α) treatment in reducing total HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV-) coinfected patients from the Swiss HIV Cohort Study and the Zurich Primary HIV Infection Study. Unique to other studies, they included patients from 3 groups: (1) HIV-1 chronic; (2) HIV-1 acute (both stratified according to time to initiation of ART after HIV-1 infection); and (3) a no-ART HIV-1–infected group.

Total HIV-1 DNA was quantified in 247 samples with a mean number of time points (range) per patient of 6.6 (2-12), 5.6 (2-10), and 5.7 (3-9) in the chronic, acute, and no-ART groups, respectively. In no-ART patients, pIFN-α treatment decreased the HIV-1 RNA viral load by 0.8 log10 on average. Pre-pIFN-α HIV-1 DNA levels were on average 0.66 log higher in the chronic versus the acute group. Total HIV-1 DNA levels remained stable before, during, and after pIFN-α treatment in all three groups.

In conclusion, the study did not reveal any effect of pIFN-α on the latent reservoir as measured by total HIV-1 DNA in PBMCs. The study-results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 latent reservoir.


18th April Lodi et al., Immediate initiation of antiretroviral treatment

Effect of immediate initiation of antiretroviral treatment on the risk of acquired HIV drug resistance.    AIDS

Lodi et al. on behalf of the HIV-CAUSAL collaboration aimed to estimate and to compare the 7-year risks of acquired drug resistance under immediate antiretroviral therapy (ART) initiation and the previously recommended CD4+ cell count-based initiation strategies. The authors defined acquired drug resistance using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation.

In 50’981 eligible individuals, 10% had CD4+ cell count more than 500 cells/ml at baseline, and 63% initiated ART during follow-up. Of 2’672 tests for acquired drug resistance, 794 (30%) found resistance. The estimated 7-year risk of acquired drug resistance was 3.2% for immediate initiation, 3.1% for initiation with CD4 + cell count less than 500 cells/ml, and 2.8% for initiation with CD4+ cell count less than 350 cells/ml. In analyses restricted to individuals with baseline in 2005–2015, the corresponding estimates were 1.9%, 1.9%, and 1.8%.

In conclusion, the study-results show that the risk of acquired drug resistance was similar under immediate and delayed ART initiation. Compared with ART initiation with CD4+ less than 500 cells/ml or AIDS and CD4+ less than 350 cells/ml or AIDS, immediate ART initiation increased the 7-year risk of acquired drug resistance by only 0.13 and 0.37%, respectively. The estimated 7-year risk of clinically identified acquired drug resistance was approximately 3% under all ART initiation strategies. These risks and risk differences were even lower in individuals with initial CD4+ cell count more than 500 cells/ml and individuals who entered the study after 2004.


12th April Aebi-Popp et al., Post-treatment HCV antibody dynamics

Rapid decline of anti-HCV antibodies following early treatment of incident HCV infections in HIV-infected MSM.    HIV Medicine

Aebi-Popp et al. investigated HCV antibody level dynamics following an incident HCV infection in HIV-infected MSM with different clinical outcomes: treatment-induced sustained virological response (SVR), spontaneous clearance, and untreated HCV infection progressing to chronic infection.

At baseline, median HCV antibody levels were similar in the three groups. Over 3 years of follow-up, SVR was associated with a more pronounced decrease in anti-HCV levels compared with spontaneous clearance and untreated infection [median decline 71% [interquartile range (IQR: 43–87%), 38% (IQR: 29–60%) and 12% (IQR: 9–22%), respectively; P < 0.001]. Seroreversions occurred in five of 33 (15%) patients with SVR and in one of 12 (8%) with spontaneous clearance. A shorter delay between time of infection and treatment start correlated with higher rates of decline in antibody levels. Seven (16%) patients with treatment-induced or spontaneous HCV clearance experienced a reinfection, and all but one had detectable HCV antibodies before reinfection.

In conclusion, SVR was associated with a more pronounced decline in anti-HCV antibody levels and with a higher frequency of seroreversions compared with spontaneous clearance or untreated replicating HCV infection among HIV-infected MSM with incident HCV infections. The high rate of reinfections in patients with detectable HCV antibodies before reinfection suggest that detectable HCV antibodies do not confer protection against reinfection.


11th April Tarr et al., Subclinical coronary artery disease in Swiss HIV+ and HIV- persons

Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons.   European Heart Journal

Tarr et al. aimed to compare the prevalence of subclinical atherosclerosis in HIV-positive and HIV-negative persons in Switzerland using coronary artery calcium (CAC)/computed tomography angiography (CCTA), and to assess associations between cardiovascular risk factors, HIV infection, and subclinical coronary artery disease. They enrolled 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA.

HIV-positive participants were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score > 0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/ mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; P < 0.01], lower coronary segment severity score (aOR 0.72; P = 0.04), and lower segment involvement score (aOR 0.71; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; P = 0.02).

In conclusion, in this study HIV infection was not associated with more subclinical atherosclerosis. On the contrary, HIV was associated with less calcified coronary plaques and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores. In addition, the study found no evidence of advanced coronary age in HIV-positive patients, and thus was unable to confirm previous reports. Taken together, these reports somewhat attenuate concerns about accelerated subclinical atherosclerosis in HIV-positive persons.


5th April Rasmussen et al., Phylodynamics on networks

Phylodynamics on local sexual contact networks.    PLOS Computational Biology

Phylodynamic models are widely used in infectious disease epidemiology to infer the dynamics and structure of pathogen populations. However, these models generally assume that individual hosts contact one another at random, ignoring the fact that many pathogens spread through highly structured contact networks.

In the current work, Rasmussen et al. presented a new framework for phylodynamics on local contact networks based on pairwise epidemiological models that track the status of pairs of nodes in the network rather than just individuals. By considering how local interactions among hosts shape the phylogeny of a pathogen, their models offered a “pathogen's eye view” of these networks. By considering pathogen phylogenies in a probabilistic framework, these coalescent models could also be used to estimate the statistical properties of contact networks directly from phylogenies using likelihood-based inference. The authors used this framework to explore how much information phylogenies retain about the underlying structure of contact networks and to infer the structure of a sexual contact network underlying a large HIV-1 sub-epidemic in Switzerland.

In conclusion, the authors provided a simple theoretical framework to explore the relationship between contact networks, epidemic dynamics, and phylogenies. They showed that phylodynamic modeling framework provides a good approximation to the coalescent process on random networks and can recapitulate the major features of pathogen phylogenies simulated on different types of random graphs.

pdf publication

4th April Congratulations!

It is with great pleasure that we can inform you on two projects that will be supported by the Swiss National Science Foundation for the coming years.

  • The role of sexual behaviour dynamics and treatment-as-prevention in the spread of HIV, Hepatitis C and syphilis: Predicting the conditions for control and elimination
    (Principal Investigator: Andri Rauch, CHF 686’074.- for 4 years)

  • HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance
    (Principal Investigator: Huldrych Günthard, CHF 834’889.- for 3 years)

This shows that research conducted in the SHCS is continuously highly competitive and is considered worth to be funded!

Best wishes,

Huldrych Günthard
President of the SHCS

28th March Prague et al., Dynamic models for estimating the effect of HAART on CD4 in observational studies

Dynamic models for estimating the effect of HAART on CD4 in observational studies: Application to the Aquitaine Cohort and the Swiss HIV Cohort Study.     Biometrics

Prague et al. aimed to estimate the effect of HAART on CD4 count using four dynamic models and compared estimates with those from a naive regression model. In their work, they presented three discrete-time dynamic models based on linear increments models (LIM): the first one based on one difference equation for CD4 counts, the second with an equilibrium point, and the third based on a system of two difference equations, which allowed jointly modeling CD4 counts and viral load. The authors considered continuous-time models based on ordinary differential equations with non-linear mixed effects (ODE-NLME). They compared the different approaches in simulation and in illustration on the ANRS CO3 Aquitaine Cohort and the Swiss HIV Cohort Study.

The authors found that the proposed mechanistic models allowed incorporating biological knowledge when available, which lead to increased statistical evidence for detecting treatment effect. Because inference in ODE-NLME was numerically challenging and required specific methods and softwares, LIM were a valuable intermediary option in terms of consistency, precision, and complexity.

pdf publication

22nd March Nakagawa et al., Estimating number living with HIV in the United Kingdom

An epidemiological modelling study to estimate the composition of HIV-positive populations including migrants from endemic settings.   AIDS

Nakagawa et al. aimed to demonstrate a novel approach using a mathematical model with the United Kingdom (UK) as an example, to present key public health outputs on the national level, including the size of the undiagnosed population and HIV incidence. They used an individual-based stochastic simulation model to calibrate to routinely collected surveillance data in the UK.

An estimated 106’400 people were living with HIV in the UK in 2013. Twenty-three percent of these people, 24’600 (90% plausibility range: 15’000–36’200) were estimated to be undiagnosed; this number has remained stable over the last decade. An estimated 32% of the total undiagnosed population had CD4+ cell count less than 350 cells/ml in 2013. Twenty-five and 23% of black African men and women heterosexuals living with HIV were undiagnosed respectively.

In conclusion, the authors presented a method to generate national-level estimates about the size and characteristics of HIV-positive populations incorporating migrants from sub-Saharan Africa. These estimates should help inform and evaluate current and future public health responses to the epidemic by providing more information about the affected population than can be understood and achieved solely from surveillance.


21st March McLaren et al., Exome sequencing and HIV-1 control

Evaluating the impact of functional genetic variation on HIV-1 control.   Journal of Infectious Diseases

Human genetic variation plays a large role in determining the outcome of HIV-1 infection. However, common, genome-wide genetic factors identified by genome-wide association studies can only explain up to 25% of the observed variability in HIV setpoint viral load.

To assess the evidence for an additional impact of functional variation in HIV progression, McLaren et al. combined exome sequence data across 5 independent studies that evaluated 3 related models of HIV control in a total of 1’327 individuals with high-quality data.

The authors found that multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations.

In conclusion, the study-results suggest that exomic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.


15th March Monge et al., Immunovirological response to cART in migrants

Immunological and virological response to antiretroviral treatment in migrant and native men and women in Western Europe; is benefit equal for all?   HIV Medicine

Monge et al. on behalf of COHERE in EuroCoord aimed to evaluate differences in immunovirological response to combination antiretroviral therapy (cART) in migrant and native men and women.

Of 32’817 individuals, 25’799 (78.6%) were men. The percentage of migrants was higher in women (48.9%) than in men (21.2%) and migrants from sub-Saharan Africa accounted for the largest migrant group (29.9% in men and 63.3% in women). Migrant men and women from sub-Saharan Africa started at lower CD4 cell counts than native individuals, which remained lower over time. Virological response was ≥ 85% at 12 months for all groups except Caribbean women (77.7%). Compared with native individuals men and women, lower virological response was experienced by North Africa and the Middle East (subdistribution hazard ratios [sHR] 0.91] and sub-Saharan Africa (sHR 0.88) men and Caribbean (sHR 0.77) women, respectively.

In conclusion, immunovirological response to cART in Western Europe varies by geographical origin and sex of patients. The study-results have implications for clinical management and policy changes regarding earlier HIV testing and cART entitlement; they can help clinicians be alert to particular groups, especially women, who will require extra support with their treatments.


14th March Boyd et al., Combined CVD and CKD risk in the D:A:D study

Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study.   PLoS Medicine

The D:A:D study has developed specific models to predict the risk for CVD and CKD events in HIV-positive people. Boyd et al. on behalf of the D:A:D study aimed to study whether participants in D:A:D at high (>5%) predicted risk for both cardiovascular disease (CVD) and chronic kidney disease (CKD) would be at even greater risk for CVD and CKD events.

CKD was defined as confirmed estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2. The authors calculated the CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%±5%, >5%). A total of 27,215 participants contributed 202,034 person-years of follow-up. Participants at high CVD risk had a 5.63-fold (p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction.

In conclusion, the study found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD compared with those at low predicted risk for both, and those at high predicted risk for only CVD or only CKD. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results should further encourage clinicians to prioritize addressing modifiable risks for CVD and CKD in HIV-positive people.

pdf publication

5th March Wittkop et al., CD4 cell count response to first-line cART in HIV-2+ versus HIV-1+ patients

CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: a multinational, multicohort European study.   Journal of Antimicrobial Chemotherapy

Wittkop et al. on behalf of the COHERE in EuroCoord and the ACHIeV2e Study Group aimed to assess CD4 cell recovery following first-line combination ART (cART) in HIV-2+ infected individuals compared to HIV-1+ infected individuals. ART-naive HIV+ adults were included, if they started first-line combination antiretroviral therapy (without NNRTIs or fusion inhibitors) between 1997 and 2011.

Overall, the study included 185 HIV-2+ and 3’0321 HIV-1+ patients with a median age of 46 years and 37 years, respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 in HIV-2+ patients and in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12months were 105 in HIV-2 patients and 202 in HIV-1 patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower in HIV-2 patients compared with HIV-1 patients.

In conclusion, differences in CD4 cell dynamics between HIV-2 and HIV-1 were consistent in all analyses, with a poorer CD4 cell increase after start of treatment in HIV-2 patients, even after adjustment for pretreatment plasma viral load. The study-results underline the need to identify other factors contributing to this lower CD4 cell response, such as more potent drugs against HIV-2, adapted to the particularities of the virus replication when compared with HIV-1, in order to improve case management.

pdf publication

1st March Veit et al., Yellow fever vaccine in HIV-infected individuals

Long-term immune response to yellow fever vaccination in HIV-infected individuals depends on HIV-RNA suppression status: Implications for vaccination schedule.    Clinical Infectious Diseases

Veit et al. studied the immune response over time to yellow fever vaccination (YFV) and the necessity for booster vaccination in 247 HIV-infected individuals from the Swiss HIV Cohort Study. A plaque reduction neutralization titer (PRNT) of 1:≥10 was regarded as reactive and protective.

At vaccination, 82% of the vaccinees were taking combination antiretroviral therapy (cART), 83% had suppressed HIV RNA levels (<400 copies/mL), and their median CD4 T-cell count was 536 cells/μL. PRNT was reactive in 46% before, 95% (95% CI, 91%–98%) within 1 year, 86% at 5 years, and 75% at 10 years postvaccination. In those with suppressed plasma HIV RNA at YFV, the proportion with reactive PRNTs remained high: 99% within 1 year, 99 at 5 years, and 100% at 10 years.

In conclusion, the study-results suggest that long-term immune response up to 10 years to YFV is primarily dependent on the control of HIV replication at the time of vaccination. Vaccinees on successful cART had high levels of reactive PRNT, and protective titers were maintained up to 10 years. The results point toward acceptable safety of YFV in HIV-infected individuals on cART. Until further data on long-term immunity are available, the authors recommend that HIV-infected patients should be vaccinated against YF once their HIV RNA is suppressed and receive a YFV booster after 10 years if they stay on uninterrupted successful cART to restimulate the vaccine response. However, HIV-infected persons who were vaccinated with replicating HIV should either have their PRNT measured or receive a booster YFV while on successful cART, irrespective of time elapsed since primary YFV.


28th February Congratulations to Gilles Wandeler!

It is with great pleasure that we can inform you that Gilles Wandeler, MD from the Inselspital Bern, received one of the highly competitive SNF professorships for his project

Towards the functional cure of hepatitis B virus infection

Congratulations to Gilles Wandeler!

Great to have you on board Gilles, and we wish you all the best for this exciting project!

Kind regards,

Huldrych Günthard,
President of the SHCS

22nd February Thorne et al., Coinfection with HIV and HCV in children and young adults living in Europe

Coinfection with HIV and hepatitis C virus in 229 children and young adults living in Europe.     AIDS

Thorne et al. on behalf of EuroCoord aimed to conduct a study of HIV/hepatitis C virus (HCV) coinfection in children, adolescents and young adults infected with HIV/HCV vertically or before age 18 years to characterize this subpopulation with respect to mode of acquisition, HCV genotype, clinical status and treatment.

Of 229 patients included, 62% had vertically acquired infection. Median age at last follow-up was 16.2 years. Most children had HCV genotype 1 (55%) or 3 (31%). One-fifth had a previous AIDS diagnosis. At their last clinic visit, 70% had no/mild immunosuppression (CDC stage 1), and 73% on antiretroviral therapy had undetectable HIV RNA. Overall, 55% had alanine aminotransferase levels of more than 40 IU/l at their last test. Of 97 patients with transient elastography, 12 had results of more than 9 kPa; this was associated with duration of HCV infection (P=0.033), but not with CD4+ cell count, antiretroviral therapy use or sex in univariable analysis. Of 17 patients with liver biopsies, six had bridging fibrosis and one had cirrhosis. The SVR24 rates among the individuals treated with pegylated interferon and ribavirin were 32% (8/25) for genotype 1 and 79% (15/19) for genotype 3; the one treated patient with genotype 2 achieved an SVR24, but none of the three treated patients with genotype 4 did so.

In conclusion, the current study is the first one describing a large population of HIV/HCV coinfected children and young people across Europe. As clinical management of coinfected children has previously relied on extrapolation from adult studies, the findings will contribute to better understanding of this coinfection in childhood. The study describes a substantial proportion of HIV/HCV coinfected children and young people with progressive liver disease, with low response to standard treatment with pegIFN/RBV among the minority treated to date.

Considering this, the improved life expectancy in HIV-infected children and the excellent outcomes in adults with HIV/HCV infection treated with direct acting agents, illustrate the need for these HCV treatments in HIV/HCV coinfected children.


21st February Ryom et al., eGFR after chronic renal impairment

Predictors of eGFR progression, stabilisation or improvement after chronic renal impairment in HIV-positive individuals.    AIDS

Ryom et al. on behalf of the D:A:D study group aimed to investigate the improvement in estimated glomerular filtration rate (eGFR) after development of chronic renal impairment (CRI) in HIV-positive individuals. The median of all eGFRs measured 24–36 months after CRI was compared with the median eGFR defining CRI, and changes were grouped into improvement (>+10 ml/min), stabilization (-10 to +10 ml/min) and progression (

Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilized and 12% progressed. Individuals remaining on tenofovir (TDF) or atazanavir boosted with ritonavir ATV/r 24 months post-CRI had worse eGFR outcomes compared with those unexposed (TDF: 0.47 and ATV/r: 0.63). Individuals off TDF for 12-24 months or off ATV/r for more than 12 months had similar eGFR outcomes as those unexposed to these antiretrovirals. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes.

In conclusion, the study-results suggest that eGFR improvement after CRI is relatively common, with one in five individuals experiencing significant eGFR improvement, and 23% experiencing complete resolution of CRI. Likewise, most HIV-positive individuals progressing to CRI subsequently stabilized eGFR at moderate levels of renal impairment rather than continued to decline. These observations offer reassurance for HIV-positive persons and their healthcare providers, as it seems that at least some of the excess renal risk among HIV-positive persons can be modified with appropriate management.


14th February Rhee et al., Mutational correlates of virological failure in individuals receiving WHO-recommended tenofovir-containing regimen

Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen: an international collaboration.    EBioMedicine

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure on a WHO-recommended TDF-containing first-line regimen. Rhee et al. aimed to identify TDF regimen-associated mutations (TRAMs) by comparing the proportion of each reverse transcriptase mutation in 2’873 individuals with virological failure on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50’803 antiretroviral-naïve individuals.

The authors identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen: A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F.

In conclusion, the study shows that the spectrum of TDF-selected mutations extends beyond K65R/N and K70E/G/Q. Several of the additional TDF-selected mutations are non-polymorphic mutations that are currently not considered surveillance drug resistance mutations yet may be important for monitoring TDF associated transmitted drug-resistance. Additionally, the clinical significance of several mutations that occurred commonly in combination with K65R including A62V, S68G/N/D, L74I, V75L and Y115F requires further phenotypic and clinical studies to better understand their effects on both TDF and the newly developed prodrug tenofovir alafenamide (TAF).

pdf publication

1st February Caniglia et al., Comparison of monitoring strategies based on CD4 cell counts in virally suppressed HIV-positive individuals

Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study.     Lancet HIV

Caniglia et al. on behalf of the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems aimed to establish whether information about an individual’s time-varying CD4 cell count can provide any additional benefit in determining when monitoring frequency can be decreased.

The authors compared three strategies using different CD4 cell count thresholds to determine whether CD4 cell count and HIV RNA viral load was measured every 3–6 months (when below the threshold) or every 9–12 months (when above the threshold). The threshold was 200 cells per μL in the first strategy, 350 cells per μL in the second strategy, and 500 cells per μL in the third strategy.

They found that the different strategies had no effect on survival, AIDS-free survival, and mean CD4 cell count at 2 years, suggesting that decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of HIV-positive individuals with viral suppression. However, the authors found that decreasing monitoring frequency when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL results in an increased risk of virological failure at 2 years. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2.01 (1.17–3.43) for threshold 200 and 1.24 (0.89–1.73) for threshold 350.

In conclusion, the study-results suggest that in virologically suppressed individuals on ART in resource-rich settings, the CD4 threshold at which monitoring frequency can be decreased to annually might be as low as 200 cells per μL with no effect on clinical and immunological outcomes after 2 years. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further research is warranted to obtain more precise effect estimates over longer periods of follow-up, and to determine the generalisability of these results to resource-limited settings.


29th January Lodi et al., Immediate ART in older HIV positive patients

Effect of immediate initiation of antiretroviral treatment in HIV-positive individuals aged 50 years or older.    Journal of Acquired Immune Deficiency Syndromes

Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants.

Lodi et al. on behalf of the HIV-CAUSAL Collaboration of HIV cohorts from Europe and the Americas aimed to estimate the 5-year risk of all-cause mortality and non-AIDS mortality among ART-naive, AIDS-free individuals aged between 50 and 70 years.

The study included 9’596 individuals (28% US Veterans) with median age of 55 (52–60) years and CD4 count of 336 (182–513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: 20.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3.

In conclusion, immediate initiation of ART seems to be beneficial in reducing all-cause mortality in AIDS-free patients aged 50 years or older, despite their low baseline CD4 count. More effort should be made into diagnosing HIV earlier, particularly in older patients to ensure timely initiation of treatment and follow-up for concomitant comorbidities, thereby maximizing the benefit of early treatment for HIV.


25th January Leitman et al., HLA-B*14:02-env-restricted CD8+ T-cells in HIV control

HLA-B*14:02-restricted env-specific CD8+ T-cell activity has highly potent antiviral efficacy associated with immune control of HIV infection.    Journal of Virology

Immune control of HIV infection is typically associated with effective Gag-specific CD8+ T-cell responses. To investigate further the potential role of non-Gag-specific CD8+ T-cell responses in control of HIV infection, Leitman et al. focused here on HLA-B*14, where the dominant HIV-specific CD8+ T-cell response is in Env but not Gag specific.

The authors demonstrated that Env-specific HLA-B*14-restricted activity was substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV were observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This was reflected by an increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, they showed that HLA-B*14:02 was significantly more strongly associated with viremic control than HLA-B*14:01.

In conclusion, the studies indicate that, although Gag-specific CD8+ T-cell responses may usually have greater antiviral efficacy against HIV for the several reasons described above, influences such as functional avidity of individual responses are also critically important factors that may override protein specificity in contributing to immune control of HIV infection. This finding is relevant to the development of vaccines designed to generate effective antiviral CD8+ T-cell responses.

pdf publication

18th January Del Amo et al., Educational level and response to antiretroviral treatment

Inequalities by educational level in response to combination antiretroviral treatment and survival in HIV-positive men and women in Europe (1996-2013): a collaborative cohort study.    AIDS

Del Amo et al. on behalf of COHERE in Euro-Coord aimed to investigate differences by educational level in virological and immunological response to combined antiretroviral treatment (cART), as well as incidence of all-cause mortality and new AIDS-defining events in HIV-positive men and women in COHERE data from 1996 to 2013.

Of 24’069 HIV-positive patients, 9% had not completed primary education, 32% had completed primary, 44% secondary, and 15% tertiary education. Overall, 21% were women, who were overrepresented in lower educational strata. During 132’507 person-years of follow-up, 1’081 individuals died; cumulative mortality decreased with higher educational level (P<0.001). Over 122 765 person-years, new AIDS events or death occurred in 2598 individuals; differences by education were more marked than for death alone (P<0.001). Virological response was achieved by 67% of patients without completed basic education, 85% with completed primary education, 82% with secondary, and 87% with tertiary (P<0.001). Patients with higher education had higher CD4+ cell count at cART initiation and at each time after cART but rate of CD4+ cell count recovery did not differ.

In conclusion, the study-results support the argument for sustained educational efforts at the European level to improve active citizenship, social cohesion, and health impacting on the macro-level determinants. They also reinforce the need for proximal down-stream interventions on clinical and preventive care among less educated HIV-positive patients once they are linked to care to address inequities.

pdf publication

17th January Bouteloup et al., Reference curves for CD4 response

Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.      HIV Medicine

Bouteloup et al. on behalf of COHERE in EuroCoord aimed to provide ‘reference curves’ for CD4 T-cell responses during the first 12 months of combination antiretroviral therapy (cART) for patients with virological suppression, according to the characteristics of the patients at cART initiation. Data on 27 cohorts across 35 European countries were provided for the present analysis. All persons aged ≥ 18 years who started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL 6 months after cART initiation were included in the study.

A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249. The median observed CD4 counts at 6, 9 and 12 months were 382, 402 and 420 cells/lL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL was generally required in order that patients stayed ‘on track’ (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those who started with CD4 counts in the higher percentiles.

In conclusion, the study proposes reference curves for the CD4 count that may be used as an additional tool for the clinician when evaluating responses to cART. A web tool is available at http://shiny.isped.u-bordeaux.fr/CD4refcurves


11th January Monge et al., Combined antiretroviral treatment in migrants in Europe

Timing of cART initiation in male and female migrants living with HIV in Western Europe: an observational cohort study (1997-2013).    AIDS

The Migrant Health Working Group on behalf of COHERE in EuroCoord aimed to evaluate differences in timing of combined antiretroviral treatment (cART) initiation by geographical origin in male and female HIV-positive patients in COHERE. They included 151 674 individuals (72.9% men) from Western Europe between January 1997 and March 2013, with known geographical origin and at least 1 CD4+ cell count measurement while cART-naïve.

Median CD4+ cell count falls far below 250 cells/ml in all groups and was lowest in sub-Saharan African (SSA: 161), Caribbean men (161) and in Asian women (185). Among men, the adjusted probability of cART initiation was lower in migrants compared with natives, but differences depended on initial CD4+ cell count. In women, no meaningful differences were observed between natives and most migrant groups. However, SSA women had a 31% higher probability of cART initiation when recruited at a CD4+ more than 500 cells/ml and 9% (4–14%) lower when recruited at CD4+ less than 100 cells/ml.

In conclusion, the study-results highlight late initiation of cART in the migrant population in Western Europe and differences in timing of cART initiation for some groups within migrant communities, especially for men. Addressing existing barriers to access HIV testing and care and ensuring universal and free access to cART is important to advance in the elimination of inequities and in the control of the HIV epidemic in Western Europe.


10th January Judd et al., Triple-class failure by age and perinatal HIV

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.    HIV Medicine

Judd et al. on behalf of COHERE in EuroCoord aimed to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection.

A total of 5’972 participants starting antiretroviral therapy (ART) from 1998, aged 500 HIV-1 RNA copies/mL despite ≥4 months of use.

The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall (17 vs. 8 weeks) and highest in perinatally infected participants aged 10–14 years (49 weeks). The cumulative proportion with TCVF 5 years after starting ART was 9.6% in participants with perinatally acquired infection and 4.7% in participants with heterosexually acquired infection. Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI based initial regimens, higher pre-ART viral load and lower pre-ART CD4.

In conclusion, for participants with perinatal HIV infection, these findings indicate the need to diagnose and start ART earlier in childhood, and adopt a strategic approach in ART selection to prevent the emergence of resistance. These measures may help children and adolescents achieve and sustain virological suppression as they approach adulthood.

pdf publication

4th January Stirrup et al., Predictors of CD4 recovery following initiation of ART

Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion.     HIV Medicine

Stirrup et al. on behalf of CASCADE Collaboration in EuroCoord aimed to investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. They used data from the CASCADE multinational cohort collaboration of HIV-1 seroconverters and analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003 - March 2014 (n=7600).

The authors found that “true’ CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. Use of an integrase-inhibitor regimen at treatment initiation was found to be associated with a moderate improvement in post-treatment recovery in CD4 relative to the NNRTI regimen.

In conclusion, CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid. The finding that higher plasma VL at treatment initiation predicts more rapid CD4 cell recovers is maybe explained by some evidenced that higher VL levels are associated with sequestration of CD4 cells in lymphoid tissue and that this is associated with a more rapid initial increase in circulating CD4 cells following the initiation of cART.


3rd January Trickey et al., CD4:CD8 and CD8 as Markers for Mortality

CD4:CD8 ratio and CD8 count as prognostic markers for mortality in Human Immunodeficiency Virus–infected patients on antiretroviral therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC).    Clinical Infectious Diseases

Trickey et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to investigate whether the CD4:CD8 ratio or CD8 counts were independently associated with all-cause, AIDS, and non-AIDS mortality in patients treated with antiretroviral therapy (ART) with suppressed viral load and CD4 count >350 cells/μL For the analysis, the authors combined data from 13 European and North American cohorts participating in the Antiretroviral Therapy Cohort Collaboration.

During 276’526 person-years, 1’834 of 49’865 patients (3.7%) died (249 AIDS-related; 1’076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11. The association of CD8 count with all-cause mortality was U-shaped with a higher mortality for those with higher and lower values compared with those with values near the median (aHR 1.13 and 1.11, respectively). AIDS related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count.

In conclusion, the study does not lend strong support to use CD4:CD8 ratio and CD8 count as a prognostic marker for non-AIDS related mortality in virally suppressed patients on ART. However, the failure of many patients in this long-term treated HIV-infected population to reach the levels of CD4:CD8 ratio or CD8 count considered to be normal in the general population may indicate ongoing immune dysregulation. This may have longer-term consequences than the authors have been able to study here, or associations may be only with specific causes of death.