Cohort Profile: The Zurich Primary HIV Infection Study.

The Zurich Primary HIV Infection (ZPHI) study is a longitudinal cohort study established in 2002, aiming to study the clinical, epidemiological, and biological characteristics of primary HIV infection. The ZPHI enrolls individuals with documented primary HIV-1 infection. At the baseline and thereafter, the socio-demographic, clinical, and laboratory data are systematically collected, and regular blood sampling is performed for biobanking. By the end of December 2022, 486 people were enrolled, of which 353 were still undergoing active follow-up. Of the 486 participants, 86% had an acute infection, and 14% a recent HIV-1 infection. Men who have sex with men accounted for 74% of the study population. The median time from the estimated date of infection to diagnosis was 32 days. The median time from diagnosis to the initiation of antiretroviral therapy was 11 days, and this has consistently decreased over the last two decades. During the seroconversion phase, 447 (92%) patients reported having symptoms, of which only 73% of the patients were classified as having typical acute retroviral syndrome. The ZPHI study is a well-characterized cohort belonging to the most extensively studied primary HIV infection cohort. Its findings contribute to advancing our understanding of the early stages of HIV infection and pathogenesis, and it is paving the way to further improve HIV translational research and HIV medicine.

Late outcome after surgical and topical treatment for Aspergillus mediastinitis after heart transplantation.

The 7-year long-term survival after Aspergillus fumigatus mediastinitis after heart transplantation, an uncommonly described condition, is herein reported. A 66-year-old male developed an infection with A. fumigatus covering the entire thoracic cavity with a fungal turf after orthotopic heart transplantation. Repeated surgical removal of infectious and necrotic tissue together with innovative topical treatment using voriconazole and chlorhexidine combined with systemic antifungal treatment, helped in controlling the infection. Definitive wound closure was achieved by standard sternal refixation and latissimus dorsi muscle flap plasty. Survival after A. fumigatus mediastinitis after heart transplantation was achieved with sequential debridement in combination with topical application of antifungal agents.

A Treatment-as-Prevention Trial to Eliminate Hepatitis C Among Men Who Have Sex With Men Living With Human Immunodeficiency Virus (HIV) in the Swiss HIV Cohort Study.

BACKGROUND: In 2016, the World Health Organization (WHO) introduced global targets for the elimination of hepatitis C virus (HCV) by 2030. We conducted a nationwide HCV micro-elimination program among men who have sex with men (MSM) living with human immunodeficiency virus (HIV) from the Swiss HIV Cohort Study (SHCS) to test whether the WHO goals are achievable in this population. METHODS: During phase A (10/2015-06/2016), we performed a population-based and systematic screening for HCV-RNA among MSM from the SHCS. During phase B (06/2016-02/2017) we offered treatment with HCV direct-acting antiviral (DAA) agents to MSM identified with a replicating HCV infection. During phase C (03/2017-11/2017), we offered rescreening to all MSM for HCV-RNA and initiated DAA treatment in MSM with replicating infections. RESULTS: We screened 3715/4640 (80%) MSM and identified 177 with replicating HCV infections (4.8%); 150 (85%) of whom started DAA treatment and 149 (99.3%) were cured. We rescreened 2930/3538 (83%) MSM with a prior negative HCV-RNA and identified 13 (0.4%) with a new HCV infection. At the end of the micro-elimination program, 176/190 MSM (93%) were cured, and the HCV incidence rate declined from .53 per 100 patient-years (95% CI, .35-.83) prior to the intervention to .12 (95% CI, .03-.49) by the end of 2019. CONCLUSIONS: A systematic, population-based HCV micro-elimination program among MSM living with HIV was feasible and resulted in a strong decline in HCV incidence and prevalence. Our study can serve as a model for other countries aiming to achieve the WHO HCV elimination targets. CLINICAL TRIALS REGISTRATION: NCT02785666.

Emergence of Resistance to Integrase Strand Transfer Inhibitors during Dolutegravir Containing Triple-Therapy in a Treatment-Experienced Patient with Pre-Existing M184V/I Mutation.

With the current widespread use of dolutegravir in low-income countries, the understanding of the impact of nucleoside reverse transcriptase inhibitor (NRTI-) associated mutations on the efficacy of dolutegravir-containing antiretroviral therapy (ART) is of utmost importance. We describe a rare case of a patient with pre-existing M184V/I mutation and virological failure on a dolutegravir/lamivudine/abacavir regimen with the emergence of integrase strand transfer inhibitor resistance mutations. Additional risk factors, which may have triggered the virological failure, included suboptimal adherence and low nadir CD4+ cell count. This case illustrates that dolutegravir-containing triple-therapy should be prescribed with caution to patients with pre-existing M184V/I mutation and poor efficacy of the reverse transcriptase inhibitor backbone. In addition, this case highlights the need for viral load monitoring in patients on dolutegravir-containing regimens in settings with a high prevalence of the M184V/I mutation such as in low-income countries.

Screening HIV-positive men who have sex with men for hepatitis C re-infection risk: is a single question on condom-use enough? A sensitivity analysis.

BACKGROUND: Hepatitis C virus (HCV) is common in men who have sex with men (MSM) with HIV. The Swiss HCVree Trial targeted a micro-elimination by using a treat and counsel strategy. Self-reported condomless anal intercourse with non-steady partners was used as the selection criterion for participation in a counselling intervention designed to prevent HCV re-infection. The purpose of this study was to assess the ability of this criterion to identify men who engaged in other sexual risk behaviours associated with HCV re-infection. METHODS: Men who disclosed their sexual and drug- use behaviours during the prior 6 months, at study baseline, were included in the current study. Using a descriptive comparative study design, we explored self-reported sexual and drug-use risk behaviours, compared the odds of reporting each behaviour in men who reported and denied condomless anal intercourse with non-steady partners during the prior year and calculated the sensitivity/specificity (95% CI) of the screening question in relation to the other at-risk behaviours. RESULTS: Seventy-two (61%) of the 118 men meeting eligibity criteria reported condomless anal intercourse with non-steady partners during the prior year. Many also engaged in other potential HCV transmission risk behaviours, e.g., 52 (44%) had used drugs. In participants disclosing drug use, 44 (37%) reported sexualised drug use and 17 (14%) injected drugs. Unadjusted odds ratios (95% CI) for two well-known risk behaviours were 2.02 (0.80, 5.62) for fisting and 5.66 (1.49, 37.12) for injecting drug use. The odds ratio for sexualised drug use - a potential mediator for increased sexual risk taking - was 5.90 (2.44, 16.05). Condomless anal intercourse with non-steady partners showed varying sensitivity in relation to the other risk behaviours examined (66.7-88.2%). CONCLUSIONS: Although condomless anal intercourse with non-steady partners was fairly sensitive in detecting other HCV relevant risk behaviours, using it as the only screening criterion could lead to missing a proportion of HIV-positive men at risk for HCV re-infection due to other behaviours. This work also points to the importance of providing access to behavioral interventions addressing other sexual and drug use practices as part of HCV treatment. TRIAL REGISTRATION: Clinical Trial Number: NCT02785666 , 30.05.2016.

Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial.

BACKGROUND: Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy. METHODS: EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%. RESULTS: Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, -100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level. CONCLUSION: In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART. CLINICAL TRIALS REGISTRATION: NCT02551523.

High Cure Rates With Grazoprevir-Elbasvir With or Without Ribavirin Guided by Genotypic Resistance Testing Among Human Immunodeficiency Virus/Hepatitis C Virus-coinfected Men Who Have Sex With Men.

Background: This study was performed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance-associated substitutions (RASs) in the Swiss HCVree Trial. Methods: We performed hepatitis C virus (HCV) RNA screening among all men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4-infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention. Results: We screened 3722 MSM and identified 177 (4.8%) with replicating infection. A total of 122 individuals (3.3%) were eligible for study treatment. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk counseling program. Conclusions: Grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin, achieved high cure rates and had an excellent safety profile. Unique to other studies, the treatment duration was guided by the presence of baseline RASs among genotype 1a-infected individuals, and the treatment phase was accompanied by an HCV risk reduction-oriented behavioral intervention. This successful population-wide treatment approach lays the groundwork to achieve HCV elimination in coinfected MSM. Clinical Trials Registration: NCT02785666.

High Number of Potential Transmitters Revealed in a Population-based Systematic Hepatitis C Virus RNA Screening Among Human Immunodeficiency Virus-infected Men Who Have Sex With Men.

Background: The proportion of undiagnosed hepatitis C virus (HCV) infections in high-risk populations, such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) is unclear. Identification of potential HCV transmitters is important to reach World Health Organization HCV elimination targets. Methods: Between October 2015 and May 2016, we performed a systematic HCV RNA-based screening among HIV-infected MSM participating in the Swiss HIV Cohort Study (SHCS). HCV antibodies were measured from all HCV RNA-positive samples. Results: Of 4257 MSM recorded in the SHCS database, we screened 3722 (87%) by HCV polymerase chain reaction, and 177 (4.8%) harbored a replicating HCV infection. We identified 24 individuals (14%) with incident HCV infection; one-third of them had a negative HCV antibody result at the time of HCV RNA positivity. In a multivariable model, elevated liver enzyme values (odds ratio, 14.52; 95% confidence interval, 9.92-21.26), unprotected sex with occasional partners (2.01; 1.36-2.98), intravenous drug use (7.13; 4.36-11.64), noninjectable drug use (1.94; 1.3-2.88), and previous syphilis diagnosis (2.56; 1.74-3.76) were associated with HCV RNA positivity. Conclusions: A systematic HCV RNA-based screening among HIV-infected MSM revealed a high number of potential transmitters. A substantial subpopulation of MSM had incident infection, one-third of whom had a negative HCV antibody test result at the time of the HCV RNA positivity. These data reveal that one-time RNA testing of a high-risk population for HCV RNA might identify more infected persons than routine testing for HCV antibodies and liver enzymes. Clinical Trials Registration: NCT02785666.

Associations Between Antiretroviral Treatment and Avascular Bone Necrosis: The Swiss HIV Cohort Study.

BACKGROUND: HIV-infected individuals have an increased risk of avascular bone necrosis (AVN). Antiretroviral therapy (ART) and particularly protease inhibitors (PI) have been implicated as a risk factor. We aimed to study the associations of ART with the occurrence of AVN among Swiss HIV Cohort Study participants (SHCS). METHODS: We used incidence density sampling to perform a case control study within the Swiss HIV Cohort Study (SHCS) comparing prospectively collected AVN cases and controls by conditional logistic regression analysis. To evaluate the effect of ART, multivariable models were adjusted for HIV transmission risk group, age, alcohol consumption, use of corticosteroids, CD4 nadir, maximum viral load, and pancreatitis. RESULTS: We compared 74 AVN cases and 145 controls. Associations with AVN were shown for heterosexual HIV acquisition (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.1-10), alcohol consumption (OR, 2.7; 95% CI, 1.3-5.7), and hyperlipidemia (OR, 3.6; 95% CI, 1.4-9.6). After adding ART substances to the multivariable base model, there was evidence of an association for treatment with tenofovir (TDF) >1 year (OR, 4.4; 95% CI, 1.4-14) with AVN. Neither exposure to specific frequently prescribed ART combinations or ART drug classes nor cumulative ART exposure showed any associations with AVN. CONCLUSIONS: In the HIV-infected population, a combination of risk factors such as heterosexual HIV acquisition, moderate to severe alcohol intake, and hyperlipidemia seem to contribute to AVN. ART does not seem to be a relevant risk factor for AVN. The association of prolonged TDF exposure with AVN needs to be confirmed.

[Hoarsness after a trip to the United States of America]. / Heiserkeit nach USA-Reise.

A 52 year old Swiss presented with a sore throat and progressive hoarseness. The histology showed a granulomatous inflammation of the epiglottis. Microbiology revealed dimorphic fungi in the sputum which were identified as Histoplasma sp. The histoplasma antigen was positive in urine and serum. Antimycotic therapy with itraconazol p.o. was started and switched to Amphotericin B i. v. due to clinical deterioration. Adrenal insufficiency should be considered in any patient with disseminated histoplasmosis since both the infection as well as the antimycotic treatment may cause Morbus Addison. An alternative therapy for the disseminated histoplasmosis is voriconazol. The investigation of the travel history is an important point.

High prevalence of anorectal chlamydial infection in HIV-infected men who have sex with men in Switzerland.

Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) were enrolled in an anorectal Chlamydia trachomatis screening study. Anorectal Chlamydia DNA was detected in 16 (10.9%) of 147 men, mainly among asymptomatic patients and patients having >20 sexual partners. These results support routine anorectal Chlamydia screening in HIV-infected MSM who report unprotected anal intercourse.

Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study.

BACKGROUND: Noncirrhotic portal hypertension (NCPH) is a newly described life-threatening liver disease of unknown cause in human immunodeficiency virus (HIV)-infected persons. Postulated pathogenesis includes prolonged exposure to antiretroviral therapy, particularly didanosine. METHODS: We performed a nested case-control study including 15 patients with NCPH and 75 matched control subjects of the Swiss HIV Cohort Study to investigate risk factors for the development of NCPH. Matching criteria were similar duration of HIV infection, absence of viral hepatitis, and follow-up to at least the date of NCPH diagnosis in the respective case. RESULTS: All 15 case patients had endoscopically documented esophageal varices and absence of liver cirrhosis on biopsies; 4 died because of hepatic complications. At NCPH diagnosis, case patients and control subjects were similar concerning sex; race; Centers for Disease Control and Prevention stage; HIV-RNA level; CD4 cell count nadir; and lipids and lipodystrophy. Differences were found in age (conditional logistic regression odds ratio [OR] for 10 years older, 2.9; 95% confidence interval [CI], 1.4-6.1); homosexuality (OR, 4.5; 95% CI, 1.2-17); current CD4 cell count <200 cells/microL (OR, 34.3; 95% CI, 4.3-277); diabetes mellitus (OR, 8.8; 95% CI, 1.6-49); alanine aminotransferase level higher than normal (OR, 13.0; 95% CI, 2.7-63); alkaline phosphatase higher than normal (OR, 18.3; 95% CI, 4.0-85); and platelets lower than normal (OR, 20.5; 95% CI, 2.4-178). Cumulative exposure to antiretroviral therapy (OR per year, 1.3; 95% CI, 1.0-1.6), nucleoside reverse-transcriptase inhibitor (OR, 1.3; 95% CI, 1.1-1.7), didanosine (OR, 3.4; 95% CI, 1.5-8.1), ritonavir (OR, 1.4; 95% CI, 1.0-1.9), and nelfinavir (OR, 1.4; 95% CI, 1.0-1.9) were longer in case patients. Exposure to nonnucleoside reverse-transcriptase inhibitor and other protease inhibitors were not different between groups. In bivariable models, only the association of NCPH with didanosine exposure was robust; other covariables were not independent risk factors. CONCLUSIONS: We found a strong association between prolonged exposure to didanosine and the development of NCPH.

Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8 T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma.

Partial deletion of CYP2B6 owing to unequal crossover with CYP2B7.

OBJECTIVE: To evaluate the possibility of copy number variation (CNV) of CYP2B6. METHODS: We investigated CNV in 226 HIV-1-infected individuals by quantitative PCR. Identification of a candidate CNV prompted characterization of the size of deletion by assessment of absence of exons, mapping of the recombination site by sequencing, and by southern blot. The functional consequences of CNV were assessed in silico (predicted protein), and in vivo, by evaluation of plasma drug levels of the CYP2B6 substrate efavirenz. RESULTS: Analyses identified one white individual carrying a heterozygous deletion of exons 1-4 of CYP2B6. We identified a approximately 68 kb deletion between CYP2B7 and CYP2B6, and mapped the crossover to a homologous region in intron 4 of both genes. The new hybrid allele, named CYP2B6*29, carries two amino acid substitutions, Q172H and M198T, previously associated with impaired enzyme function. Consistent with the functional prediction, the average of efavirenz area under the curve values of the patient was mean+/-SD, 81.64+/-23.62, versus 47.75+/-19.73 mug h/ml for individuals with an extensive metabolizer phenotype. CONCLUSION: CYP2B6*29 represents a new mechanism of genetic variation at the CYP2B6 locus, underscoring the highly polymorphic nature of this isoenzyme.

HIV replication elicits little cytopathic effects in vivo: analysis of surrogate markers for virus production, cytotoxic T cell response and infected cell death.

Several potential mechanisms for viral destruction of HIV-infected cells have been described. The hypothesis was examined that if HIV were cytopathic, a positive relation between the in vivo virus production or CTL activity and infected cell death should be observed. In a regression analysis no significant relation was found between surrogate markers for in vivo virus production or the virus-specific CTL response and death rates of productively infected cells. In a subgroup of patients the hypothesis is rejected that HIV replication elicits a large (R(2) > 0.25) cytopathic effect (P < 0.05, N = 36). It is concluded that HIV replication elicits little cytopathic effect in productively infected cells and that CD4(+) T lymphocytes are eroded by other mechanisms.

Tenofovir-containing nucleoside/nucleotide-only antiretroviral maintenance therapy: decision making and virological outcome.

OBJECTIVE: To assess the virological outcome of patients with undetectable human immunodeficiency (HI) viremia switched to tenofovir (TDF)-containing nucleosideonly (NUKE-only) treatments and to investigate the factors influencing the physicians' decision for application of a nonestablished therapy. METHOD: Patients' characteristics and history were taken from the cohort database. To study the decision-making process, questionnaires were sent to all treating physicians. RESULTS: 49 patients were changed to TDF-containing NUKE-only treatment and 46 had a follow-up measurement of HI viremia. Virological failure occurred in 16 (35%) patients. Virological failure was associated with previous mono or dual therapy and with a regimen including didanosine or abacavir. No failure occurred in 15 patients without these predisposing factors. The main reasons for change to TDF-containing NUKE-only treatment were side effects and presumed favorable toxicity profile. The rationale behind this decision was mainly analogy to the zidovudine/lamivudine/abacavir maintenance therapy. CONCLUSION: TDF-containing NUKE-only treatment is associated with high early failure rates in patients with previous nucleoside reverse transcriptase inhibitor mono or dual therapy and in drug combinations containing didanosine or abacavir but not in patients without these predisposing factors. In HIV medicine, treatment strategies that are not evidence-based are followed by a minority of experienced physicians and are driven by patients' needs, mainly to minimize treatment side effects.

Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study.

OBJECTIVES: To assess the long-term safety of discontinuation of secondary anti-Pneumocystis prophylaxis in HIV-infected adults treated with antiretroviral combination therapy and who have a sustained increase in CD4 cell counts. DESIGN: Prospective observational multicentre study. PATIENTS AND METHODS: The incidence of P. jirovecii pneumonia after discontinuation of secondary prophylaxis was studied in 78 HIV-infected patients on antiretroviral combination therapy after they experienced a sustained increase in CD4 cell counts to at least 200 x 10(6) cells/l and 14% of total lymphocytes measured twice at least 12 weeks apart. RESULTS: Secondary prophylaxis was discontinued at a median CD4 cell count of 380 x 10(6) cells/l. The median follow-up period after discontinuation of secondary prophylaxis was 40.2 months, yielding a total of 235 person-years of follow-up. No cases of recurrent P. jirovecii pneumonia occurred during this period. The incidence was thus 0 per 100 person-years with a 95% upper of confidence limit of 1.3 cases per 100 patient-years. CONCLUSIONS: Discontinuation of secondary prophylaxis against P. jirovecii pneumonia is safe even in the long term in patients who have a sustained immunologic response on antiretroviral combination therapy.

Antiretroviral treatment and osteonecrosis in patients of the Swiss HIV Cohort Study: a nested case-control study.

We examined risk factors for avascular bone necrosis (AVN) particularly focusing o the question of whether antiretroviral treatment (ART) is associated with the emergence of osteonecrosis. After 11 years of following the entire cohort, 26 patients were found to have AVN. Compared to 260 concurrent HIV-infected controls, at risk when cases were diagnosed, patients with AVN had lower CD4 cell count nadirs (median 86.5 versus 137.5 cells/microl, p = 0.010) and suffered significantly more often from Pneumocystis pneumonia, cerebral toxoplasmosis, CMV retinitis, and atypical mycobacteriosis and had a significantly higher body mass index than controls. Duration of ART before AVN was not significantly different between cases and controls (2.92 versus 2.17 years, p = 0.30). In conclusion, AVN could not be attributed to time on antiretroviral treatment, but patients with AVN had histories of more severe immunosuppression and a higher body mass index than controls.