Obesity trends and body mass index changes after starting antiretroviral treatment : the Swiss HIV Cohort Study

BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir <199 cells/µL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/µL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited.

Management of hepatitis C virus (HCV) infection in drug substitution programs.

BACKGROUND: In Switzerland, intravenous drug use (IDU) accounts for 80% of newly acquired hepatitis C virus (HCV) infections. Early HCV treatment has the potential to interrupt the transmission chain and reduce morbidity/mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programs are often insufficiently screened and treated. OBJECTIVE/METHODS: With the aim to improve HCV management in IDUs, we conducted a cross sectional chart review in three opioid substitution programs in St. Gallen (125 methadone and 71 heroin recipients). Results were compared with another heroin substitution program in Bern (202 patients) and SCCS/SHCS data. RESULTS: Among the methadone/heroin recipients in St. Gallen, diagnostic workup of HCV was better than expected: HCV/HIV-status was unknown in only 1% (2/196), HCV RNA was not performed in 9% (13/146) of anti-HCV-positives and the genotype missing in 15% (12/78) of HCV RNA-positives. In those without spontaneous clearance (two thirds), HCV treatment uptake was 23% (21/91) (HIV-: 29% (20/68), HIV+: 4% (1/23)), which was lower than in methadone/heroin recipients and particularly non-IDUs within the SCCS/SHCS, but higher than in the, mainly psychiatrically focussed, heroin substitution program in Bern (8%). Sustained virological response (SVR) rates were comparable in all settings (overall: 50%, genotype 1: 35-40%, genotype 3: two thirds). In St. Gallen, the median delay from the estimated date of infection (IDU start) to first diagnosis was 10 years and to treatment was another 7.5 years. CONCLUSIONS: Future efforts need to focus on earlier HCV diagnosis and improvement of treatment uptake among patients in drug substitution programs, particularly if patients are HIV-co-infected. New potent drugs might facilitate the decision to initiate treatment.

Impact of a Nurse Vaccination Program on Hepatitis B Immunity in a Swiss HIV Clinic.

ABSTRACT: We evaluated the impact of a nurse program for hepatitis B virus vaccination in a center from the Swiss HIV Cohort Study. Immunity (anti-HBs >10 IU/mL) increased from 32% to 76% in the intervention center (n = 238) where vaccine management was endorsed by nurses, but only from 33% to 39% in control centers (n = 2712, P < 0.001) where management remained in charge of physicians. Immunity against HBV in the HIV population is insufficient in Switzerland. Specific nurse vaccination program may efficiently improve health care.

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

Background: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. <p>Objective: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. Methods: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. Results: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/mu l; P= 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (Cl) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7(95%Cl, 1.2-11.3) and 5.9 (95% Cl, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log(10)copies/ml, respectively, compared with < 2.2 log(10)copies/ml. Conclusions: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Incidence of HIV-1 drug resistance among antiretroviral treatment-naive individuals starting modern therapy combinations.

BACKGROUND: Estimates of drug resistance incidence to modern first-line combination antiretroviral therapies against human immunodeficiency virus (HIV) type 1 are complicated by limited availability of genotypic drug resistance tests (GRTs) and uncertain timing of resistance emergence. METHODS: Five first-line combinations were studied (all paired with lamivudine or emtricitabine): efavirenz (EFV) plus zidovudine (AZT) (n = 524); EFV plus tenofovir (TDF) (n = 615); lopinavir (LPV) plus AZT (n = 573); LPV plus TDF (n = 301); and ritonavir-boosted atazanavir (ATZ/r) plus TDF (n = 250). Virological treatment outcomes were classified into 3 risk strata for emergence of resistance, based on whether undetectable HIV RNA levels were maintained during therapy and, if not, whether viral loads were >500 copies/mL during treatment. Probabilities for presence of resistance mutations were estimated from GRTs (n = 2876) according to risk stratum and therapy received at time of testing. On the basis of these data, events of resistance emergence were imputed for each individual and were assessed using survival analysis. Imputation was repeated 100 times, and results were summarized by median values (2.5th-97.5th percentile range). RESULTS: Six years after treatment initiation, EFV plus AZT showed the highest cumulative resistance incidence (16%) of all regimens (<11%). Confounder-adjusted Cox regression confirmed that first-line EFV plus AZT (reference) was associated with a higher median hazard for resistance emergence, compared with other treatments: EFV plus TDF (hazard ratio [HR], 0.57; range, 0.42-0.76), LPV plus AZT (HR, 0.63; range, 0.45-0.89), LPV plus TDF (HR, 0.55; range, 0.33-0.83), ATZ/r plus TDF (HR, 0.43; range, 0.17-0.83). Two-thirds of resistance events were associated with detectable HIV RNA level ≤500 copies/mL during treatment, and only one-third with virological failure (HIV RNA level, >500 copies/mL). CONCLUSIONS: The inclusion of TDF instead of AZT and ATZ/r was correlated with lower rates of resistance emergence, most likely because of improved tolerability and pharmacokinetics resulting from a once-daily dosage.

Exposition au VIH, à l'hépatite B et C au cabinet médical et à l'hôpital. Prévention et prophylaxie postexpositionnelle [Exposure to HIV, hepatitis B and C in office practice and hospital. Prevention and post-exposure prophylaxis]

Suite à un accident exposant à du sang (piqûre; coupure), provenant d'un patient infecté, le risque d'infection par VIH est d'environ 0,3% et par le virus de l'hépatite C (VHC) d'environ 0,5%. Chez les personnes vaccinées avec une réponse immunitaire adéquate (titre d'anticorps HBs >100 mUI/ml), aucune infection professionnelle par hépatite B n'a été reconnue en Suisse. La plupart des infections par VIH et VHB peuvent être prévenues par un traitement d'urgence et une prophylaxie postexpositionnelle (PEP). Il n'y a actuellement aucune prophylaxie postexpositionnelle pour le VHC. En cas de transmission de VHC, un traitement rapide par peginterféron et ribavirine est à envisager. Chaque hôpital et cabinet médical doivent mettre sur pied un système pour assurer une prise en charge optimale et en urgence des blessures par piqûres ou coupures. Lors de blessures accidentelles avec du sang de patients séropositifs pour le VIH et dans des situations complexes, il est recommandé de consulter un médecin du personnel ou un infectiologue expérimenté. The risk of infection after an occupational needle stick injury with blood from an infected source patient is approximately 0.3% for HIV and 0.5% for hepatitis C virus (HCV). In Switzerland no cases of occupational HBV infection have been recorded in fully vaccinated persons with a documented adequate vaccine response (HBsantibody titer >100 mIU/mL). Most occupational HIV und HBV infections can be prevented by appropriate emergency measures and post-exposure prophylaxis (PEP). No HCV-PEP is currently available. Early therapy with peginterferon and ribavirin should be considered in cases of occupational HCV seroconversion. Every hospital and office practice should establish a system for 24 h/24 h emergency management of occupational needle stick injuries. In the setting of an HIV-seropositive source patient and in complex situations, early consultation with a specialist in occupational medicine or infectious diseases should be considered.

Modulation of TCR avidity of primary HIV-1-specific CD8 T-cell responses by early and potent antiviral therapy responses

Background: CD8 T-cells play a critical role in antiviral immunity. However, mechanisms of virus control and immune correlates of protection are still not fully understood. Among other factors, TCR avidity (antigen sensitivity) is thought to play a critical role. Whereas there is a large consensus that high TCR avidity T-cell responses are correlated to higher efficacy against cancer and acute viral infections, it may be not the case in chronic persistent viral infections. Methods: TCR avidity (measured by the effect concentration 50% [EC50]) of HIV-1-specific CD8 T-cell responses directed against optimal epitopes was investigated in different cohorts of HIV-1- infected subjects (n¼114) including early acute and chronic (progressive and non-progressive) HIV-1-infection. Overall, TCR avidity was investigated in 245 HIV-1-specific CD8 T-cell responses. The relationships between TCR avidity, T-cell differentiation and functional profile including cytokine secretion, proliferation and cytotoxic potential (determined by polychromatic flow cytometry) were analyzed. Results: HIV-1-specific CD8 T-cell responses from patients with acute infection had significantly lower TCR avidity as compared to patients with chronic (progressive or non-progressive) HIVinfection (P¼0.03 and 0.003, respectively). These differences remained significant when the analyses were restricted to common epitopes (same epitopes restricted by the same class I HLA). Interestingly, some patients treated during acute infection underwent spontaneous treatment interruption. Re-exposure to high viral load induced two major effects: a) the increase in TCR avidity of pre-existing high avidity (EC50<0.01) T-cell responses (P<0.02) and b) the generation of new T-cell responses with higher TCR avidity as compared to the average pre-existing T-cell responses. Conclusion: These results suggest that high TCR avidity T-cell responses are selected during the course of HIV-1 infection and that one of the potential driving mechanisms is continuous exposure to HIV-1 antigens. These results advance our understanding of the relationship between TCR avidity and Ag exposure of antiviral memory CD8 T-cells.

The polymorphic nature of HIV type 1 env V4 affects the patterns of potential N-glycosylation sites in proviral DNA at the intrahost level.

We have previously shown that env V4 from HIV-1 plasma RNA is highly heterogeneous within a single patient, due to indel-associated polymorphism. In this study, we have analyzed the variability of V4 in proviral DNA from unfractionated PBMC and sorted T and non-T cell populations within individual patients. Our data show that the degree of sequence variability and length polymorphism in V4 from HIV provirus is even higher than we previously reported in plasma. The data also show that the sequence of V4 depends largely on the experimental approach chosen. We could observe no clear trend for compartmentalization of V4 variants in specific cell types. Of interest is the fact that some variants that had been found to be predominant in plasma were not detected in any of the cell subsets analyzed. Consistently with our observations in plasma, V3 was found to be relatively conserved at both interpatient and intrapatient level. Our data show that V4 polymorphism involving insertions and deletions in addition to point mutations results in changes in the patterns of sequons in HIV-1 proviral DNA as well as in plasma RNA. These rearrangements may result in the coexistence, within the same individual, of a swarm of different V4 regions, each characterized by a different carbohydrate surface shield. Further studies are needed to investigate the mechanism responsible for the variability observed in V4 and its role in HIV pathogenesis.

Social meets molecular: Combining phylogenetic and latent class analyses to understand HIV-1 transmission in Switzerland.

Switzerland has a complex human immunodeficiency virus (HIV) epidemic involving several populations. We examined transmission of HIV type 1 (HIV-1) in a national cohort study. Latent class analysis was used to identify socioeconomic and behavioral groups among 6,027 patients enrolled in the Swiss HIV Cohort Study between 2000 and 2011. Phylogenetic analysis of sequence data, available for 4,013 patients, was used to identify transmission clusters. Concordance between sociobehavioral groups and transmission clusters was assessed in correlation and multiple correspondence analyses. A total of 2,696 patients were infected with subtype B, 203 with subtype C, 196 with subtype A, and 733 with recombinant subtypes (mainly CRF02_AG and CRF01_AE). Latent class analysis identified 8 patient groups. Most transmission clusters of subtype B were shared between groups of gay men (groups 1-3) or between the heterosexual groups "heterosexual people of lower socioeconomic position" (group 4) and "injection drug users" (group 8). Clusters linking homosexual and heterosexual groups were associated with "older heterosexual and gay people on welfare" (group 5). "Migrant women in heterosexual partnerships" (group 6) and "heterosexual migrants on welfare" (group 7) shared non-B clusters with groups 4 and 5. Combining approaches from social and molecular epidemiology can provide insights into HIV-1 transmission and inform the design of prevention strategies.

Origin of minority drug-resistant HIV-1 variants in primary HIV-1 infection.

BACKGROUND: Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants (MVs) are present in some antiretroviral therapy (ART)-naive patients. They may result from de novo mutagenesis or transmission. To date, the latter has not been proven. METHODS: MVs were quantified by allele-specific polymerase chain reaction in 204 acute or recent seroconverters from the Zurich Primary HIV Infection study and 382 ART-naive, chronically infected patients. Phylogenetic analyses identified transmission clusters. RESULTS: Three lines of evidence were observed in support of transmission of MVs. First, potential transmitters were identified for 12 of 16 acute or recent seroconverters harboring M184V MVs. These variants were also detected in plasma and/or peripheral blood mononuclear cells at the estimated time of transmission in 3 of 4 potential transmitters who experienced virological failure accompanied by the selection of the M184V mutation before transmission. Second, prevalence between MVs harboring the frequent mutation M184V and the particularly uncommon integrase mutation N155H differed highly significantly in acute or recent seroconverters (8.2% vs 0.5%; P < .001). Third, the prevalence of less-fit M184V MVs is significantly higher in acutely or recently than in chronically HIV-1-infected patients (8.2% vs 2.5%; P = .004). CONCLUSIONS: Drug-resistant HIV-1 MVs can be transmitted. To what extent the origin-transmission vs sporadic appearance-of these variants determines their impact on ART needs to be further explored.

Antiviral Immunity in HIV-1 infected long term non-progressors (LTNPs).

Now that the acquired immunodeficiency syndrome (AIDS) epidemic is well into its second decade, it has become evident that a small percentage (approximately 5%) of HIV-infected individuals do not experience progression of HIV disease even after several years of being infected with HIV. These individuals have been designated as 'long term non-progressors' (LTNPs). From a virologic standpoint, these LTNPs have low viral burden in mononuclear cells, but persistent virus replication as manifested by chronic and generally low levels of plasma viremia. From an immunologic standpoint, immune functions including CD8(+) T-cell- and CD4(+) T-cell-mediated functions are preserved. In addition, they show a vigorous humoral immune response. More importantly, lymphoid tissue structure and function are preserved in LTNPs. Despite persistent low-level virus replication and chronic stimulation of the immune system, immune activation is qualitatively and quantitatively different in LTNPs compared to that observed in HIV-infected individuals whose HIV disease has progressed.

Genomic approaches to the study of HIV‐1 acquisition.

Host genome studies are increasingly available for the study of infectious disease susceptibility. Current technologies include large-scale genotyping, genome-wide screens such as transcriptome and silencing (silencing RNA) studies, and increasingly, the possibility to sequence complete genomes. These approaches are of interest for the study of individuals who remain uninfected despite documented exposure to human immunodeficiency virus type 1. The main limitation remains the ascertainment of exposure and establishing large cohorts of informative individuals. The pattern of enrichment for CCR5 Δ32 homozygosis should serve as the standard for assessing the extent to which a given cohort (of white subjects) includes a large proportion of exposed uninfected individuals.

High prevalence of peripheral arterial disease in HIV-infected persons

BACKGROUND: Atherosclerosis has been assessed in human immunodeficiency virus (HIV)-infected persons by using various methods. Peripheral arterial disease (PAD) has not been evaluated, however. We studied the cross-sectional prevalence of lower limb PAD in an HIV-infected population. METHODS: PAD was assessed using the Edinburgh Claudication Questionnaire and by measuring the systolic ankle-brachial blood pressure index (ABI) at rest and after exercise. Patients with PAD were further evaluated by duplex scan of lower limb arteries. RESULTS: Ninety-two consecutive HIV-infected patients were evaluated (23.9% women; mean age, 49.5 years; 61.9% current smokers). Claudication was reported by 15.2% of the patients. PAD was found in 20.7% of the patients: 9.8% had an abnormal ABI (<0.90) at rest, and 10.9% had normal ABI at rest but a >25% decrease after exercise. Of the patients with PAD, 84.2% were investigated with duplex scan, all of whom had atherosclerotic occlusions or stenoses of the iliac or femoral arteries. Age, diabetes, smoking, and low CD4+ T lymphocyte counts were identified as independent predictors of PAD. CONCLUSIONS: The prevalence of symptomatic and asymptomatic PAD is high in the HIV-infected population and is much higher than expected (prevalence in the general population, approximately 3% at 60 years). This study suggests the presence of an epidemic of PAD approximately 20 years earlier in the HIV-infected than in the general population. Larger epidemiological studies are needed to better define risk factors and to evaluate whether PAD is associated with increased mortality, as it is in the general population.

Accumulation of human immunodeficiency virus-specific cytotoxic T lymphocytes away from the predominant site of virus replication during primary infection.

Down-regulation of the initial burst of viremia during primary human immunodeficiency virus (HIV) infection is thought to be mediated predominantly by HIV-specific CD8+ cytotoxic T lymphocytes (CTL). This response is associated with major perturbations in the T cell receptor (TCR) repertoire. To investigate the failure of the cellular immune response to adequately control viral spread and replication and to prevent establishment of HIV infection, changes in the TCR repertoire and in the distribution of virus-specific CTL between blood and lymph node were analyzed in three patients with primary infection. By the combined use of clonotype-specific polymerase chain reaction and analysis of the frequency of in vivo activated HIV-specific CTL, it was shown that HIV-specific CTL clones preferentially accumulated in blood as opposed to lymph node. Accumulation of HIV-specific CTL in blood occurred prior to effective down-regulation of virus replication in both blood and lymph node. These findings should provide new insights into how HIV, and possibly other viruses, elude the immune response of the host during primary infection.

EV02: a Phase I trial to compare the safety and immunogenicity of HIV DNA-C prime-NYVAC-C boost to NYVAC-C alone.

The aim of this randomised controlled trial was to see if the addition of 4 mg/ml DNA-C priming given by the intramuscular route at weeks 0 and 4 to NYVAC-C at weeks 20 and 24, safely increased the proportion of participants with HIV-specific T-cell responses measured by the interferon (IFN)-gamma ELISpot assay at weeks 26 and/or 28 compared to NYVAC-C alone. Although 2 individuals discontinued after the first DNA-C due to adverse events (1 vaso-vagal; 1 transient, asymptomatic elevation in alanine transaminase), the vaccines were well tolerated. Three others failed to complete the regimen (1 changed her mind; 2 lost to follow-up). Of the 35 that completed the regimen 90% (18/20) in the DNA-C group had ELISpot responses compared to 33% (5/15) that received NYVAC-C alone (p=0.001). Responses were to envelope in the majority (21/23). Of the 9 individuals with responses to envelope and other peptides, 8 were in the DNA-C group. These promising results suggest that DNA-C was an effective priming agent, that merits further investigation.