Cohort Profile: The Zurich Primary HIV Infection Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Design
2.2. Primary Objectivies and Outcomes
- To investigate and describe the factors which could influence the course of PHI and the factors that, in turn, could be influenced by PHI.
- To expand the established biobank to be used as a base for future research questions and projects.
2.3. Inclusion Criteria
2.4. Data Collection and Project Measures
2.5. Ethical Considerations and Study Protocols
2.6. Antiretroviral Treatment
3. Results
3.1. Enrolment, Rentention, and Mortality
3.2. Socio-Demographic and Baseline Characteristics
3.3. Presentation of PHI
3.4. Antiretroviral Treatment Simplification
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
References
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ZPHI | Total | Acute Infection | Recent Infection |
---|---|---|---|
No. of patients ever registered | 486 (100) | 419 (86.2) | 67 (13.8) |
Sex a | |||
Male patients | 459 (94.4) | 397 (94.8) | 62 (92.5) |
Female patients | 27 (5.6) | 22 (5.3) | 5 (7.5) |
Ethnicity | |||
White | 418 (86.0) | 365 (87.1) | 53 (79.1) |
Hispano-American | 30 (6.2) | 25 (6.0) | 5 (7.4) |
Black | 21 (4.3) | 18 (4.3) | 3 (9.0) |
Asian | 9 (1.9) | 5 (1.2) | 4 (6.0) |
Other/unknown | 8 (1.6) | 6 (1.4) | 2 (3.0) |
Patients under active follow-up | |||
Active patients | 353 (72.6) | 302 (72.1) | 51 (76.1) |
Loss to follow-up | |||
Total | 133 (100) | 117 (100) | 16 (100) |
Left ZPHI network | 94 (70.7) | 85 (72.6) | 9 (56.3) |
Patient did not respond to invitation | 19 (14.3) | 16 (13.7) | 3 (18.8) |
Death | 18 (13.5) | 15 (12.8) | 3 (18.8) |
Other | 2 (1.5) | 1 (0.9) | 1 (6.3) |
Center of registration | |||
University Hospital Zurich | 401 (82.5) | 347 (82.8) | 54 (80.6) |
Center for Infectious Diseases Zurich | 47 (9.7) | 35 (8.4) | 12 (17.9) |
Checkpoint Zurich | 19 (3.9) | 18 (4.3) | 1 (1.5) |
City Hospital Zurich | 8 (1.6) | 8 (1.9) | 0 (0) |
Arztpraxis Kalkbreite b | 7 (1.4) | 7 (1.7) | 0 (0) |
Other | 4 (0.8) | 4 (1.0) | 0 (0) |
Most likely route of infection | |||
MSM | 361 (74.3) | 309 (73.7) | 52 (77.6) |
Heterosexual sex | 92 (18.9) | 80 (19.1) | 12 (17.9) |
Injection drug use | 25 (5.1) | 22 (5.3) | 3 (4.4) |
Needle injury | 3 (0.6) | 3 (0.7) | 0 (0) |
Other/unknown | 5 (1.0) | 5 (1.2) | 0 (0) |
Time from estimated Infection to diagnosis (days) | |||
Median | 32 | 28 | 119 |
IQR | (21–62) | (20–45) | (101–142) |
Age at HIV Diagnosis (years) | |||
Mean (median) | 36 (34) | 36 (35) | 36 (33) |
IQR | (28–42) | (28–42) | (26–43) |
Opportunistic infections at diagnosis | |||
Total | 28 (5.8) | 23 (5.5) | 5 (7.5) |
Patients with CDC B-events | 18 (3.7) | 15 (3.6) | 3 (4.5) |
Patients with CDC C-events | 10 (2.1) | 8 (1.9) | 2 (3.0) |
HIV viral load at diagnosis (log copies/mL) | |||
Mean (median) | 5.52 (5.49) | 5.57 (5.58) | 5.15 (5.08) |
IQR | (4.71–6.53) | (4.80–6.59) | (4.51–5.89) |
CD4+ cell count at diagnosis (cells/µL) | |||
Mean (median) | 470 (409) | 427 (408) | 464 (418) |
IQR | (297–533) | (290–521) | (337–582) |
HIV Subtype | |||
B | 328/454 (72.2) | 284/391 (72.6) | 44 (69.8) |
CRF01_AE | 40/454 (8.8) | 35/391 (9.0) | 5/63 (7.9) |
A1 | 19/454 (4.2) | 15/391 (3.8) | 4/63 (6.3) |
C | 16/454 (3.5) | 13/391 (3.3) | 3/63 (4.8) |
F1 | 13/454 (2.9) | 12/391 (3.1) | 1/63 (2.3) |
Other | 38/454 (8.4) | 32/391 (8.2) | 6/63 (9.5) |
Time from estimated infection to treatment (days) | |||
Median | 49 | 43 | 136 |
IQR | (31–90.5) | (29–71) | (123–179) |
Time from HIV diagnosis to treatment (days) | |||
Median | 11 | 11 | 18 |
IQR | (7–24) | (6–22) | (9–42) |
Number of patients exposed to cART | 485 (99.8) | 418 (99.8) | 67 (100) |
CD4+ cell count at start of cART (cells/µL) | |||
Mean (median) | 428 (389) | 424 (381) | 453 (406) |
IQR | (288–532) | (286–525) | (310–547) |
Time from cART initiation to suppressed viral load (under 50 copies/mL), (days) | |||
Mean (median) | 103.2 (89) | 108.4 (96.5) | 67 (56) |
IQR | (56–138) | (58–141) | (32–87) |
ZPHI | 2002 | 2007 | 2012 | 2017 | 2022 |
---|---|---|---|---|---|
No. of active patients | 27 | 140 | 238 | 332 | 353 |
Gender | |||||
Male patients | 22 (81.5) | 124 (88.6) | 224 (94.1) | 313 (94.3) | 336 (95.2) |
Female patients | 5 (18.5) | 16 (11.4) | 14 (5.9) | 19 (5.7) | 17 (4.8) |
Ethnicity | |||||
Caucasian | 24 (88.9) | 122 (87.1) | 209 (87.8) | 290 (87.3) | 310 (87.8) |
Hispano-American | 0 (0) | 8 (5.7) | 13 (5.5) | 18 (5.4) | 16 (4.5) |
Black | 2 (7.4) | 7 (5) | 11 (4.6) | 13 (3.9) | 12 (3.4) |
Asian | 1 (3.7) | 2 (1.4) | 3 (1.3) | 6 (1.8) | 8 (2.3) |
Other/unknown | 0 (0) | 1 (0.7) | 2 (0.8) | 5 (1.5) | 7 (2.0) |
Most likely route of infection | |||||
MSM | 13 (48.1) | 100 (71.4) | 187 (78.6) | 256 (77.1) | 270 (76.5) |
Heterosexual sex | 12 (44.4) | 34 (24.3) | 43 (18.1) | 63 (19.0) | 57 (16.2) |
Injection drug use | 0 (0) | 3 (2.1) | 4 (1.7) | 8 (2.4) | 19 (5.4) |
Needle injury | 2 (7.4) | 3 (2.1) | 3 (1.3) | 2 (0.6) | 2 (0.6) |
Other/unknown | 0 (0) | 0 (0) | 1 (0.4) | 3 (0.9) | 5 (1.4) |
Age (years) | |||||
Mean (median) | 36.3 (33) | 39.6 (39) | 40.9 (40) | 43.9 (44) | 47.2 (47) |
Infection type at diagnosis | |||||
Acute infection | 25 (92.6) | 126 (90) | 212 (89.1) | 284 (85.5) | 302 (85.6) |
Recent infection | 2 (7.4) | 14 (10) | 26 (10.9) | 48 (14.5) | 51 (14.4) |
Viral load < 50 cps/mL (%) | 16 (59.3) | 88 (62.9) | 208 (87.4) | 325 (97.9) | 344 (97.5) |
Viral load < 400 cps/mL (%) | 19 (70.4) | 95 (67.9) | 222 (93.3) | 331 (99.7) | 350 (99.2) |
On cART | 21 (77.8) | 131 (93.6) | 234 (98.3) | 330 (99.4) | 351 (99.4) |
All N = 486 | Acute N = 419 | Recent N = 67 | |
---|---|---|---|
General PHI Manifestation | |||
Symptomatic | 447/486 (92.0) | 389/419 (92.8) | 58/67 (86.6) |
Typical ARS | 347/479 (72.4) | 306/414 (73.9) | 41/65 (63.1) |
Atypical ARS | 100/479 (20.9) | 83/414 (20.0) | 17/65 (26.2) |
Hospitalisation | 77/486 (15.8) | 73/419 (17.4) | 4/67 (6.0) |
Clinical Manifestation | |||
Fever | 352/485 (72.6) | 318/419 (75.9) | 34/66 (51.5) |
Malaise | 305/467 (65.3) | 273/407 (67.1) | 32/60 (53.3) |
Rash | 198/483 (41.0) | 181/417 (43.4) | 17/66 (25.8) |
Headache | 178/472 (37.7) | 153/408 (37.5) | 25/64 (39.1) |
Cough | 94/480 (19.6) | 82/416 (19.7) | 12/64 (18.8) |
Lymphadenopathy | 207/478 (43.3) | 182/413 (44.1) | 25/65 (38.5) |
Pharyngitis | 214/472 (45.3) | 194/410 (47.3) | 20/62 (32.3) |
Myalgia | 143/447 (32.0) | 131/387 (33.9) | 12/65 (18.5) |
Arthralgia | 89/446 (20.0) | 79/386 (20.5) | 10/65 (15.4) |
Vomiting | 61/472 (12.9) | 57/407 (14.0) | 4/65 (6.2) |
Night sweats | 156 /477 (32.7) | 141/412 (34.2) | 15/65 (23.1) |
Weight loss | 189 /468 (40.4) | 170/403 (42.2) | 19/65 (29.2) |
Diarrhea | 167/474 (35.2) | 152/405 (37.2) | 15 /65 (23.1) |
Nausea | 124/469 (26.4) | 115/405 (28.4) | 9/64 (14.1) |
Neurological symptoms | 52/485 (10.7) | 48/419 (11.5) | 4/66 (6.1) |
Oral ulcers | 62/470 (13.2) | 54/404 (13.4) | 8/66 (12.1) |
Genital ulcers | 27/462 (5.8) | 20/397 (5.0) | 7/65 (10.8) |
Laboratory Findings | |||
Anemia | 76/476 (16.0) | 65/411 (15.8) | 11/65 (16.9) |
Thrombopenia | 133/479 (27.8) | 125/414 (30.2) | 8/65 (12.3) |
Neutropenia | 42/450 (9.3) | 41/389 (10.5) | 1/61 (1.6) |
Leukopenia | 119/479 (24.8) | 118/414 (28.5) | 1/65 (1.5) |
Lymphopenia | 217/466 (46.6) | 199/403 (49.4) | 18/63 (28.6) |
Elevated AST | 97/455 (21.3) | 86/393 (21.9) | 11/62 (17.7) |
Elevated ALT | 148/472 (31.4) | 132/409 (32.3) | 16/63 (25.4) |
Co-infections | |||
Chlamydia | 29/454 (6.4) | 23/396 (5.8) | 6/60 (10) |
Gonorrhea | 44/462 (9.5) | 38/404(9.4) | 6/58 (10.3) |
Hepatitis B | 58/478 (12.1) | 53/413 (12.8) | 5/65 (7.7) |
Hepatitis C | 26/463 (5.6) | 21/398 (5.1) | 5/65 (7.7) |
Herpes simplex virus I+II | 11/458 (2.4) | 8/400 (2) | 3/58 (5.2) |
Syphilis | 53/476 (11.1) | 40/412 (9.7) | 13/64 (20.3) |
Total Patients with co-infections | 179/484 (37.0) | 149/418 (35.6) | 30/66 (45.5) |
Paper | Design | Methods | Main Outcome | Reference |
---|---|---|---|---|
Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies | Phase I/II study | Infusion of three neutralizing antibodies (2G12, 2F5 and 4E10) for studying suppression of viral rebound upon stop of antiretroviral treatment | Antibody-treated individuals had delayed rebound to a control group of acutely infected patients without Ab | Trkola et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nature Medicine. 2005:11:615-622 [58]. |
HIV-1 transmission after cessation of early antiretroviral therapy among men having sex with men | Molecular epidemiological population based study to identify transmissions originating from patients stopping ART | pol sequences from genotypic resistance tests and clonal env C2-V3-C3 sequences | Five new primary infection events originating from ZPHI patients within 16–61 weeks after stopping early ART | Rieder et al. HIV-1 transmission after cessation of early antiretroviral therapy among men having sex with men. AIDS. 2010;24:1177-1183 [32]. |
Ambiguous Nucleotide Calls From Population-based Sequencing of HIV-1 are a Marker for Viral Diversity and the Age of Infection | HIV sequence analysis of PWH and known infection date | Sequence analysis of partial pol sanger sequences from PWH and known infection date determining the fraction of ambiguous nucleotides | Fraction of ambiguous nucleotides is a useful marker for the age of infection | Kouyos et al. Ambiguous Nucleotide Calls From Population-based Sequencing of HIV-1 are a Marker for Viral Diversity and the Age of Infection. Clinical Infectious Diseases. 2011;52(4):532–539 [15]. |
Origin of minority drug-resistant HIV-1 variants in primary HIV-1 infection | Phylogenetic analysis | Allele specific polymerase chain reaction for drug resistance mutations in 204 acute or recent seroconverters and phylogenetic linkage to chronically infected PWH | Drug-resistant minority variants can be transmitted | Metzner et al. Origin of minority drug-resistant HIV-1 variants in primary HIV-1 infection. The Journal of Infectious Diseases. 2013;208(7):1102–1112 [55]. |
Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection | Prospective collection of clinical signs and symptoms during HIV acute infection | Characterizing typical and atypical belonging to the acute retroviral syndrom’s symptoms and signs | Unexpected clinical presentations occurred in a large fraction of PWH and a primary HIV infection | Braun et al. Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection. Clin Infect Dis. 2015 Sep 15;61(6):1013–1021 [23]. |
Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs | Comparison of phenotypic and genotypic viral characteristics of transmission pairs | Identification of probably transmission pairs, retrieving plasma and cellular samples from the biobank and phenotype and genotype HI-Virus of transmitter and recipients | No clear distinction of transmitter/founder virus from their matched transmitter viruses, suggesting stochastic transmission | Oberle et al. Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs. Retrovirology. 2016;13(1):62 [49]. |
The interplay between replication capacity of HIV-1 and surrogate markers of disease | Determination of replication capacity of 355 whole-genome primary HIV-1 isolates on primary cells | Correlation analysis between disease parameters and RC | RC correlated with set point viral load and showed significant differences between subtypes studied | Rindler et al. The interplay between replication capacity of HIV-1 and surrogate markers of disease. J Infect Dis. 2022; 226 (6), 1057–1068 [59]. |
Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): a randomized, controlled, multi-site, non-inferiority trial | Randomized, open label, non-inferiority trial | 2:1 randomization DTG monotherapy vs. continuation of cART among people starting fist cART during PHI with at least 48 weeks viral load suppression | Non-inferiority of DTG monotherapy vs. cART after 5 years of follow-up | West et al. Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): a randomized, controlled, multi-site, non-inferiority trial. Clinical Infectious Diseases. 2023; 77, 1012–1020 [24]. |
High Rates of Subsequent Asymptomatic Sexually Transmitted Infections and Risky Sexual Behaviour in Patients Initially Presenting With Primary Human Immunodeficiency Virus-1 Infection | Prospective longitudinal data collection for sexually transmitted infections (STI)’s | Systematic screening for STI’s with assessment of prevalence, incidence and clinical presentation and identification of risk factor | Very high point prevalence and incidence of STI’s with the vast majority being asymptomatic | Braun et al. High Rates of Subsequent Asymptomatic Sexually Transmitted Infections and Risky Sexual Behavior in Patients Initially Presenting With Primary Human Immunodeficiency Virus-1 Infection. Clin Infect Dis. 2018 25;217(12):1883–1888 [41]. |
Dolutegravir monotherapy as maintenance strategy: A meta-analysis of individual participant data from randomized controlled trials | Individual participant meta-analysis | Combining four randomized controlled trials evaluating dolutegravir monotherapy versus combined antiretroviral therapy (cART) among virologically individuals controlled for at least 6 months on cART | Significantly increased risk for viral failure on dolutegravir monotherapy compared to cART with D4 T cells nadir <350 mm3 having the highest adjusted hazard ratio for viral failure. | Fournier et al. Dolutegravir monotherapy as maintenance strategy: A meta-analysis of individual participant data from randomized controlled trials. Open Forum Infectious Diseases. 2022;9(6),ofac107 [60]. |
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Freind, M.C.; Tallón de Lara, C.; Kouyos, R.D.; Wimmersberger, D.; Kuster, H.; Aceto, L.; Kovari, H.; Flepp, M.; Schibli, A.; Hampel, B.; et al. Cohort Profile: The Zurich Primary HIV Infection Study. Microorganisms 2024, 12, 302. https://doi.org/10.3390/microorganisms12020302
Freind MC, Tallón de Lara C, Kouyos RD, Wimmersberger D, Kuster H, Aceto L, Kovari H, Flepp M, Schibli A, Hampel B, et al. Cohort Profile: The Zurich Primary HIV Infection Study. Microorganisms. 2024; 12(2):302. https://doi.org/10.3390/microorganisms12020302
Chicago/Turabian StyleFreind, Matt C., Carmen Tallón de Lara, Roger D. Kouyos, David Wimmersberger, Hebert Kuster, Leonardo Aceto, Helen Kovari, Markus Flepp, Adrian Schibli, Benjamin Hampel, and et al. 2024. "Cohort Profile: The Zurich Primary HIV Infection Study" Microorganisms 12, no. 2: 302. https://doi.org/10.3390/microorganisms12020302