Research Activity

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Between January 2000 and May 2011, 362 scientific projects were submitted and 266 approved for funding. Most studies were conducted with three or more centers and a large proportion of projects involved all participating centers. There has been an impressive increase in the quantity and quality of the scientific output in the years 1996-1999, and a significant increase in the past year (graph). Remarkably, the mean impact factor of the journals in which the studies were published has stabilized at a fairly high level for clinical research. This also translates into the well-recognized place of the SHCS in the international HIV field.

The SHCS is increasingly present in many international collaborations.

Overview of the SHCS clinical research activities

The scope of the studies performed within the SHCS is quite wide. However, the core interest of the SHCS relies on the study of clinical and epidemiological aspects of HIV infection. On intention, the Scientific Board of the SHCS has given only little guidance about the fields to be studied within the SHCS, but is was decided that the SHCS should support, at any given time, at least one large clinical trial that can only be performed with a large number of patients and which would not be conducted by the pharmaceutical industry. The SB also decided to build a genetic cohort  that should represent a leading research resource in HIV genomics worldwide.

In the following section, we will first summarize the SHCS focus activities and then the main studies that investigated important research questions along these lines. Beside the research along these central questions, a number of other publications have also originated from projects conducted by the SHCS.

Outside these  research focuses, investigators from all the participating centers have proposed and conducted a number of highly innovative studies that are focused on the following clinical and epidemiological aspects of HIV infection:

A selection of the most relevant results and publications is presented in the following section.

I. Genetic project

The SHCS Core Genetic project has allowed to facilitate the first 2 and subsequently the largest 3 human genome wide association study (GWAS) in the HIV-field. Furthermore a large scale transcriptome and expression polymorphism study was finished 4. GWAS undertaken in HIV/HCV coinfected and in HCV mono-infected individuals (collaboration with the Swiss Hepatitis C Cohort Study) confirmed the crucial role of genetic polymorphisms in IL28B for the natural and treatment-induced control of Hepatitis C. This study was the first GWAS investigating the role of genetic variation for spontaneous HCV clearance, and the first report on the role of IL28B in HCV/HIV-coinfected individuals 5. Several studies enlightened the role of HLA-C and CCL3L1 in HIV susceptibility 6, 7, and of HLA-alleles for the response to antiretroviral therapy as well as of TLR 9 receptor influencing the course of HIV-infection 8.

In the field of pharmacogenomics, a variety of publications addressed drug metabolism, toxicity profiles of efavirenz, atazanavir, lopinavir and abacavir 9-23.

Various SHCS projects generated genome-wide data on single nucleotide polymorphisms for over 1’000 individuals, and information on HLA-alleles is available for over 1’600 SHCS participants. This data serves for further genetic research projects. 

II. HIV-1 Drug resistance and molecular epidemiology

The SHCS genotypic drug resistance database has been built up during the grant period. The aim was the inclusion of all genotypic resistance information generated by the four laboratories performing HIV-drug resistance testing in Switzerland and the anonymous linkage of results (sequences) to the SHCS database. Standard operating procedures were implemented in 2005-2006. Since 2006 a database is available for scientific projects. Within a large retrospective sequencing project (fully financed by supplementary funds) approx. 5000 genotypes were generated in drug naive patients. Currently, more than 16000 linked sequences from almost 10’000 patients are stored.

The resistance database has been used for clinical and also more pathogenesis oriented research projects. We showed that emergence of resistance in failing treatments depends strongly on the first regimen type chosen 24. The most detailed longitudinal prevalence study for a single country available today revealed that emergence of resistance can be slowed down in a top health care environment 25 and that transmission of HIV drug resistance over a 10 year period remained stable in Switzerland 26 but that transmission of resistance can occur in clusters 27. We reported on new clinically relevant insights on resistance aspects on the new drugs etravirine 28 and raltegravir 29 and were able to demonstrate that the N348I connection domain mutation is primarily a compensatory mutation restoring fitness loss induced by emergence of the M184V mutation and mainly arises after emergence of 184V 30. Finally, we identified factors for the emergence of the important resistance mutation K65R 31 and were also able to improve the predictive power of a genotypic resistance score for response to atazanavir in salvage therapy 32. An international meta-analysis showed that less drug resistance emerges in cohorts with frequent viral load monitoring when compared to cohorts with infrequent monitoring 33. The SHCS also showed that resistance testing in treatment experienced patients is cost effective 34, 35.

To address questions of pathogenesis and transmission we take advantage of the anonymous HIV pol sequences stored in the resistance database 36-38. 

III. Clinical Trials 

A large randomized clinical trial investigating CD4-guided treatment interruption in 600 patients from Thailand and Switzerland (STACCATO Trial) was performed 39. However, a much larger trial (SMART) showed that CD4 guided treatment interruption increased mortality (centres of the SHCS have also participated in this trial) 40.

A randomized controlled trial (MOST study), conducted within the SHCS, tested the hypothesis that long-term treatment can be simplified by replacing the triple combination by a single drug having a high genetic barrier for resistance development. MOST showed that this is not possible because in the central nervous system often viral replication was noted when there was none in the periphery {Gutmann, AIDS 2010, in press}. It refuted results from a small previous non-randomized pilot study within the SHCS that formed the basis of MOST (ATARITMO study) 41.

Another study demonstrated that discontinuation of maintenance therapy against cerebral toxoplasmosis is generally safe, but may fail in a minority of patients 42.

A number of trials were also used to investigate pathogenesis related research questions. In a follow up study of the Swiss Spanish Treatment Interruption Trial (SSITT) using longitudinal clonal env sequences no signs of ongoing low level replication could be found when HIV is undetectable (detection limit of 50 copies/ml in plasma). Specific HIV sequence traits were identified for the first time that were associated with better spontaneous control of plasma viremia after stopping treatment 43, 44. In addition, low viral diversity and higher neutralizing antibody titres were associated with control of spontaneous viremia after stopping treatment and that positively selected amino-acid changes in the absence of treatment were surface exposed on gp120 and thus accessible for the immune response 45, 46.  

IV. Social Sciences and Public Health aspects

Whether genotypic drug resistance testing is cost-effective was heavily debated. A “real world” cost-effectiveness analysis 35 was performed, based on a prospective trial evaluating the effect of genotypic resistance testing on treatment response in salvage therapy 47. A model based on the whole SHCS to estimate cost-effectiveness of genotypic resistance testing was developed. We demonstrated that genotypic resistance testing for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large 34.

It was shown that despite the introduction of HAART, the suicide rate of HIV-infected patients still surpasses that one of the matched non HIV-infected Swiss population 48. A project from the MoCHIV study investigated which factors are relevant for disclosure of the HIV status in adolescents 49. A number of studies were conducted investigating behavioural and social factors associated with highly relevant adherence to treatment 50-53. A smoking cessation program was also evaluated within the SHCS 54. Behavioural changes of condom use before and after the Swiss Statement were also investigated {Hasse et al, CID, 2010, in press}. Furthermore, the impact of illicit drug use on uptake and outcome of antiretroviral therapy was studied 55. In addition, factors for late presentation of HIV-infected individuals were investigated 56. Early diagnosis should be reached by any means for several reasons: “late presenters” cause significant healthcare costs by increased morbidity, their life expectancy is reduced and undiagnosed infection represents a substantial risk of transmission. 

V. Immunology

A number of studies have addressed the role of cellular immune responses in the course of HIV-infection 57,58, in specific opportunistic infections such as in Kaposi sarcoma disease 59, JC virus infection 60 and primary CNS lymphoma 61, 62. A study about immunological predictors for abacavir hypersensitivity reactions allowed to confirm known factors and to identify an additional one 12, 63, 64. A number of immuno-genetic studies have investigated host-viral interactions in HIV/HCV co-infected patients 65-70.

One study also investigated determinants for vaccination and vaccine responses in HIV-infected children living in Switzerland 71 and revealed serious problems with vaccination coverage in this population. 

VI. Opportunistic infections, co-infections and neoplasms 

Opportunistic infections. This area of research clearly became less important within the SHCS because the incidence of these diseases has dramatically been reduced since the availability of HAART. Nevertheless, one of the most thorough longitudinal analysis of progressive multifocal leukencephalopathy (PML) included measurement of cellular immune responses for JC virus in a subgroup of patients 60, 72. A study demonstrated the importance of INH prophylaxis in patients with latent TB, and a comparison between the conventional tuberculin skin test and interferon gamma based blood tests in HIV infected patients was published 73, 74. SHCS researchers have led a multicohort analysis within the COHERE framework and showed that pneumocystis prophylaxis may not be needed in virologically suppressed patients with CD4 counts of 100-200 cells/µl 75

Resurgence of syphilis in general but also within HIV-infected patients has triggered a systematic study on incidence, prevalence and treatment modalities/success within the SHCS and showed the importance of regular serological testing in order to detect asymptomatic infections  76. A systematic prospective study revealed considerable asymptomatic infection rates with Chlamydia in MSM 77.

Hepatitis B and C co-infections. The SHCS was very active in this research area. Epidemiological and clinical research uncovered the risk of sexual transmission of HCV among MSM, the substantial barriers to HCV-therapy in HIV/HCV coinfected individuals, and the impact of hepatocellular carcinoma in the SHCS. Immunological and virological studies revealed how HCV adapts to the host’s immune responses. 5, 65-67, 69, 70, 78-82 In Hepatitis B/HIV-coinfection one study investigating liver enzyme elevations after removal of 3TC as a component of HAART, demonstrated that regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued 83.

Neoplasms. Over the last years it became evident that HIV-associated and non-HIV associated cancers may become a serious problem for the HIV-infected population in the long-term. The SHCS was at the forefront of studying cancer epidemiology but also cancer immunology in the HAART era 59, 61, 78, 82, 84-91 

VII. Drug toxicity and adverse effects of antiretrovirals

To study tolerability, long term toxicity and drug interactions of antiretrovirals was one of the key research areas of the SHCS since introduction of these drugs. Some seminal studies concerning side effects, drug-drug interactions and reasons to switch a drug regimen were published over the last years 92-96. Numerous pharmacogenetic studies were already mentioned under I. The serious problem of Tenofovir associated nephropathy was systematically studied 97, 98. Of interest, the SHCS showed for the first time that there might be an association between NNRTI use and low Vitamin D levels and demonstrated a high prevalence of severe vitamin D deficiency among HIV infected patients 99 . It was also shown that CD4 recovery in AZT treated patients is lower than if treated with other nucleosides 100.

Considerable efforts were made for better identification of factors associated with liver toxicity and in particular with non-cirrhotic portal hypertension 101, 102. Prevalence and factors associated with lipodystrophy were also assessed 103. Additionally, predictors for lactacidosis, for diabetes mellitus type II were also intensely studied 104, 105. In large multinational collaborations the SHCS has significantly contributed to studies addressing the emerging fields of cardiovascular risks, hepatotoxicity, metabolic syndrome and other drug related problems 106-112. 

VIII. Epidemiology and public health surveillance

Epidemiology. Since introduction of ART survival of HIV-infected patients has increased dramatically. The SHCS has participated in various multinational cohort studies investigating mortality and morbidity over time in the HAART era. There is also a continuous search for finding an optimal CD4 threshold for initiating antiretroviral treatment. Prognosis of patients with triple class failure was also addressed using SHCS data 113-127.

Transmission of HIV-1 in Switzerland. The most detailed and most long-term molecular epidemiological survey of HIV subtype B within a country was performed in the SHCS. It revealed that the structure of transmission chains varied significantly between transmission groups, however, there was no ongoing subtype B epidemic present in Switzerland in heterosexuals. Furthermore, needle exchange, heroin and methadone substitution programs for drug addicts reduced significantly the transmission form IDU into the heterosexual community 37. In addition, a molecular linkage study between the Zurich Primary Infection study (ZPHI) and the SHCS revealed that early antiretroviral treatment is highly efficient in lowering HIV transmission and therefore treatment during PHI will most likely have a dramatic effect on spread of infection 36. Another study revealed that an undetectable viral load is strongly predictive for a next undetectable viral load, thus, increasing confidence that suppressed patients remain non-infectious 128. 

IX. Scientific achievements of the Swiss Mother and Child study (MoCHIV-study)

During this grant period the MoCHIV study was fully integrated into the SHCS. A number of studies assessing prognostic factors, treatment related questions and toxicity related issues were studied mostly in multicohort projects due to relatively low numbers of HIV-infected children in Switzerland 129-131. Antiretroviral treatment during pregnancy and gynaecological follow up of women in the SHCS were also investigated 132, 133. Moreover, complication in caesarean section in HIV infected women, prenatal screening in pregnant HIV-1 infected women and pregnancy and delivery outcomes in Switzerland were studied 134-136 and long-term safety and efficacy of lopinavir/r in children was studied and shown to be safe 137 . 

X. Active contributions of SHCS members in treatment and management guidelines in HIV Medicine

Members of the SHCS have been actively involved in the elaboration of international guidelines for treatment 138-141 and resistance testing 142-145.

 

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