A novel index combining fecal immunochemical test, DNA test, and age improves detection of advanced colorectal adenoma.

Although the fecal immunochemical test for hemoglobin (FIT) is a widely used screening test for colorectal cancer, it is not sensitive enough to detect advanced colorectal adenoma. To address this issue, we performed this study to investigate whether combining the FIT and fecal DNA testing of methylated somatostatin (SST) could improve diagnostic performance for advanced colorectal adenoma. We collected feces from 79 healthy subjects with negative results on colonoscopy, 43 patients with non-advanced colorectal adenoma, 117 patients with advanced colorectal adenoma, and 126 patients with colorectal cancer. After fecal DNA was incubated with methylation-sensitive restriction enzymes, SST methylation levels were measured by droplet digital PCR. Using logistic multivariate analysis, we established a prediction formula for detecting colorectal neoplasia and named it the FAMS (FIT, age, methylated SST) index. The diagnostic performance of a single use of FIT for advanced colorectal adenoma showed a sensitivity of 29.1% (34/117) and specificity of 89.3% (109/122). In contrast, the FAMS index showed a sensitivity of 56.4% (66/117) at a similar specificity point of 91.0% (111/122). Furthermore, even at the higher specificity point of 94.3% (115/122), the sensitivity was still higher than that of FIT, reaching 42.7% (50/117). As the FAMS index showed better diagnostic performance for advanced colorectal adenoma than a single use of FIT, the FAMS index could be a promising tool for detecting advanced colorectal adenoma.

Sustained gut dysbiosis and intestinal inflammation show correlation with weight gain in person with chronic HIV infection on antiretroviral therapy.

BACKGROUND: Person with human immunodeficiency virus type-1 (PWH) are prone to chronic inflammation due to residual viral production, even with antiretroviral therapy (ART), which increases the risk of age-related diseases. There is also limited information on changes in the intestinal environment of PWH during ART. In this longitudinal study, we investigated changes in the gut microbiota, persistence of chronic inflammation, interactions between the gut environment and inflammation, and metabolic changes in PWH using long-term ART. RESULTS: We analyzed changes in clinical parameters and gut microbiota in 46 PWH over a mean period of 4 years to understand the influence of gut dysbiosis on inflammation. Overall, changes in the gut microbiota included a decrease in some bacteria, mainly involved in short-chain fatty acid (SCFA) production, and an increase in certain opportunistic bacteria. Throughout the study period, an increase in bacterial-specific metabolic activity was observed in the intestinal environment. Continued decline in certain bacteria belonging to the Clostridia class and metabolic changes in gut bacteria involved in glucose metabolism. Additionally, patients with a low abundance of Parabacteroides exhibited low bacterial alpha diversity and a significant increase in body mass index (BMI) during the study period. Monocyte chemoattractant protein 1, a marker of macrophage activation in the plasma, continued to increase from baseline (first stool collection timepoint) to follow-up (second stool collection timepoint), demonstrating a mild correlation with BMI. Elevated BMI was mild to moderately correlated with elevated levels of plasma interleukin 16 and chemokine ligand 13, both of which may play a role in intestinal inflammation and bacterial translocation within the gut microbiota. The rate of BMI increase correlated with the rate of decrease in certain SCFA-producing bacteria, such as Anaerostipes and Coprococcus 3. CONCLUSION: Our data suggest that despite effective ART, PWH with chronic inflammation exhibit persistent dysbiosis associated with gut inflammation, resulting in a transition to an intestinal environment with metabolic consequences. Moreover, the loss of certain bacteria such as Parabacteroides in PWH correlates with weight gain and may contribute to the development of metabolic diseases.

Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody.

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.

Characterization of proinflammatory cytokines profile during acute SARS-CoV-2 infection in people with human immunodeficiency virus.

Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were assessed in people with HIV (PWH) with effective cART. There were no significant differences in any of the tested cytokines between COVID-19 severity in PWH, while most of them were significantly higher in individuals with severe disease in HIV-uninfected individuals, suggesting that excess cytokines release by hyper-inflammatory responses does not occur in severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, especially between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that PWH are in an enhanced inflammatory state. Loss of the several inter-cytokine correlations were observed in in vitro LPS stimuli-driven cytokines production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially due to the underlying inflammatory state and/or impairment of innate immune cells.

Favorable Virological Outcome, Characteristics of Injection Site Reactions, Decrease in Renal Function Biomarkers in Asian People with HIV Receiving Long-Acting Cabotegravir Plus Rilpivirine.

Long-acting cabotegravir plus rilpivirine has revolutionized the concept of antiretroviral therapy, but as the causes of virological failure and satisfaction can depend on patient background, real-world data are needed. In this single-center study, we reviewed clinical records of people with HIV (PWH) who received injectable cabotegravir plus rilpivirine between June 2022 and January 2023. We assessed virological and safety outcomes, including injection site reactions (ISRs) and changes in serum creatinine and cystatin C. Seventy-four patients were included. There were no virological failures. Approximately 80% of individuals achieved HIV-RNA undetectable in all visits up to 14 months (median 13 months) after switching. Pain upon injection was significantly more common at the rilpivirine injection site, while delayed pain was significantly more common at the cabotegravir injection site. The serum creatinine (mean difference -0.12 mg/dL, p < .0001) and the cystatin C (mean difference -0.077 mg/dL, p < .0001) decreased significantly after switching, and in multivariable regression analysis, baseline characteristics did not affect the decrease in these renal function markers. Long-acting cabotegravir plus rilpivirine showed excellent antiviral efficacy and safety in PWH in Japan. ISRs were characterized differently at the cabotegravir and rilpivirine injection sites. Although cystatin C showed decrease after the regimen switch, further confirmation is needed whether cabotegravir plus rilpivirine can improve renal function.

Association of gut microbiota with the pathogenesis of SARS-CoV-2 Infection in people living with HIV.

BACKGROUND: People living with HIV (PLWH) with chronic inflammation may have an increasing risk for coronavirus disease 2019 (COVID-19) severity; however, the impact of their gut microbiota on COVID-19 is not fully elucidated. Here, we analyzed the temporal changes in the gut microbiota composition of hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected PLWH (PLWH-CoV) and their correlation with COVID-19 severity. RESULT: The 16S rRNA analysis results using stool samples (along the timeline from disease onset) from 12 hospitalized PLWH-CoV, whose median CD4 + T cell count was 671 cells/µl, were compared to those of 19 healthy people and 25 PLWH. Bacterial diversity in PLWH-CoV is not significantly different from that of healthy people and SARS-CoV-2 non-infected PLWH, but a significant difference in the microbiota diversity was observed in the classification according to the disease severity. Immediately after the disease onset, remarkable changes were observed in the gut microbiota of PLWH-CoV, and the changing with a decrease in some short-chain fatty acid-producing bacteria and an increase in colitis-related pathobiont. In the second week after disease onset, relative amounts of specific bacteria distinguished between disease severity. One month after the disease onset, dysbiosis of the gut microbiota persisted, and the number of Enterobacteriaceae, mainly Escherichia-Shigella, which is potentially pathogenic, increased and were enriched in patients who developed post-acute sequelae of COVID-19 (PASC). CONCLUSION: The changes in the gut microbiota associated with SARS-CoV-2 infection observed in PLWH in this study indicated a persistent decrease in SCFA-producing bacteria and an intestinal environment with an increase in opportunistic pathogens associated with enteritis. This report demonstrates that the intestinal environment in PLWH tends to show delayed improvement even after COVID-19 recovery, and highlights the importance of the dysbiosis associated with SARS-CoV-2 infection as a potential factor in the COVID-19 severity and the PASC in PLWH.

Brief communications: changes in inflammatory biomarkers and lipid profiles after switching to long-acting cabotegravir plus rilpivirine.

We assessed whether the impact of cabotegravir plus rilpivirine on inflammation reduction differs from that of oral antiretrovirals, using real-world data. Inflammatory biomarkers and lipid profiles were followed from baseline to 8 months after switching. Seventy-eight participants were analyzed. The CD4/CD8 ratio and C-reactive protein did not change. There were transient decreases in CD8 and CD4 counts in the group that switched from the dolutegravir-based regimen, but not in the tenofovir alafenamide-based regimen group. High-density lipoprotein (HDL) cholesterol increased, resulting in a decrease in the total-cholesterol to HDL cholesterol ratio, whereas there was no significant change in low-density lipoprotein cholesterol.

Attenuation of hepatitis A antibody after immunization with hepatitis A vaccine (Aimmugen) in people living with HIV.

AIM: Hepatitis A (HA) is a vaccine-preventable disease. In regions with good sanitation, men who have sex with men (MSM) are the key affected populations. During the 2018-2019 HA outbreak among MSM in Japan, we actively vaccinated MSM living with HIV (MSM-LWHIV) with Aimmugen. As previously reported, their antibody seroconversion rate due to vaccination was lower than that of healthy individuals. However, the durability of Aimmugen in people living with HIV has not yet been reported. We evaluated attenuation after the one-series vaccination (comprising three inoculations) and the factors associated with attenuation. METHODS: We retrospectively examined anti-HA immunoglobulin G (anti-HA-IgG) titers and other clinical data from our hospital's medical records. Patients with no history of vaccination or HA infection (i.e., negative HA-IgG titers) who received one series of Aimmugen, achieved seropositivity, and anti-HA-IgG antibodies were tested ≥2 years after three doses were included. Fisher's exact test and the Mann-Whitney U-test were performed. p < 0.05 was considered statistically significant. RESULTS: Fifty-one MSM-LWHIV were included. All were seropositive after the third dose with a median HA-IgG titer of 10.1 (interquartile range, 7.2-12.2) (sample/cut-off values [s/co]). In 45 (40-49) months, seropositivity decreased to 90% (46/51) and was attenuated to a median of 4.4 (2.3-6.5) s/co. Lower baseline B cell counts (p = 0.049), lower anti-HA-IgG levels after the second dose (p = 0.002), and lower anti-HA-IgG levels after the third dose (p = 0.003) were associated with seronegativity. CONCLUSIONS: Anti-HA-IgG titers of vaccinated MSM-LWHIV may be attenuated; thus, additional immunizations should be considered.

Characterization of a SARS-CoV-2 EG.5.1 clinical isolate in vitro and in vivo.

EG.5.1 is a subvariant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB variant that is rapidly increasing in prevalence worldwide. However, the pathogenicity, transmissibility, and immune evasion properties of isolates of EG.5.1 are largely unknown. Here, we show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5 in hamsters. We also demonstrate that, like XBB.1.5, EG.5.1 is transmitted more efficiently between hamsters compared to its predecessor, BA.2. In contrast, unlike XBB.1.5, we detect EG.5.1 in the lungs of four of six exposed hamsters, suggesting that the virus properties of EG.5.1 are different from those of XBB.1.5. Finally, we find that the neutralizing activity of plasma from convalescent individuals against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. Our data suggest that the different virus properties after transmission and the altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in humans.

Refractory Intestinal Behçet-Like Disease Associated with Trisomy 8 Myelodysplastic Syndrome Resolved by Parenteral Nutrition.

Intestinal Behçet disease (BD), associated with myelodysplastic syndrome (MDS), is often refractory to treatment. An 80-year-old man with trisomy 8 MDS (refractory anemia) developed intermittent fever. Despite investigations to exclude infectious disease, autoimmune disease, and malignancy as the cause of the fever, the etiology could not be determined. A colonoscopy revealed several shallow round ulcers in the ileocecal region and ascending colon, and the biopsy specimens showed nonspecific inflammation. Thereafter, the patient experienced abdominal pain and diarrhea. Other than an oral aphthous ulcer, the patient did not show symptoms to meet the diagnostic criteria for BD. The patient was diagnosed with intestinal ulcers (intestinal BD-like disease) with MDS and trisomy 8. After treatment failure with 5-aminosalicylic acid, steroid, colchicine, and azacitidine, cerebral infarction occurred. Eating was difficult because of the patient's impaired consciousness; hence, total parenteral nutrition (TPN) was commenced. The fever and abdominal symptoms improved with bowel rest over approximately 1 month. Small amounts of food were orally administered to the patient following recovery from the after-effects of the cerebral infarction, but diarrhea and fever repeatedly flared up. Therefore, TPN was continued at home. The patient has not experienced any further intestinal BD symptoms for approximately 1 year with bowel rest. Nutritional therapy, including bowel rest, may be an effective treatment option for intestinal BD with MDS, and might be used as an induction therapy of remission or a supportive therapy for other treatments.

Injection drug use and sexually transmitted infections among men who have sex with men: A retrospective cohort study at an HIV/AIDS referral hospital in Tokyo, 2013-2022.

Men who have sex with men (MSM) who use injection drugs (MSM-IDU) are at high risk of sexually transmitted infections (STIs), but the long-term incidence is unclear. We conducted a single-centre retrospective cohort study using the clinical records of non-haemophilia men with human immunodeficiency virus (HIV) who visited the Institute of Medical Science, the University of Tokyo (IMSUT) Hospital, located in Tokyo, Japan, from 2013 to 2022. We analysed 575 patients including 62 heterosexual males and 513 MSM patients, of whom 6.8% (35/513) were injection drug use (IDU). Compared to non-IDU MSM, MSM-IDU had a higher incidence of hepatitis C virus (HCV) (44.8 vs 3.5 /1,000 person-years (PY); incidence rate ratio (IRR) [95% confidence interval (95% CI)], 12.8 [5.5-29.3], p < 0.001) and syphilis (113.8 vs 53.3 /1,000 PY; IRR, 2.1 [1.4-3.1], p < 0.001). The incidence of other symptomatic STIs (amoebiasis, chlamydia, and gonorrhoea infections) was <4/1,000 PY. In multivariable Poisson regression analysis, HCV incidence was associated with MSM (IRR, 1.8 × 106 [9.9 × 105-3.4 × 106], p < 0.001), IDU (IRR, 10.1 [4.0-25.6], p < 0.001), and syphilis infection during the study period (IRR, 25.0 [1.2-518.3]/time/year, p < 0.001). Among men with HIV, the prevalence of IDU in MSM and the long-term incidence of STIs in MSM-IDU were high. IDU and sexual contact are important modes of transmission of HCV among HIV-infected MSM in Tokyo.

Airway surveillance and lung viral control by memory T cells induced by COVID-19 mRNA vaccine.

Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and hospitalization. Here, we asked whether mRNA vaccine-induced memory T cells limit lung SARS-CoV-2 replication and severe disease. We show that mice and humans receiving booster BioNTech mRNA vaccine developed potent CD8 T cell responses and showed similar kinetics of expansion and contraction of granzyme B/perforin-expressing effector CD8 T cells. Both monovalent and bivalent mRNA vaccines elicited strong expansion of a heterogeneous pool of terminal effectors and memory precursor effector CD8 T cells in spleen, inguinal and mediastinal lymph nodes, pulmonary vasculature, and most surprisingly in the airways, suggestive of systemic and regional surveillance. Furthermore, we document that: (a) CD8 T cell memory persists in multiple tissues for > 200 days; (b) following challenge with pathogenic SARS-CoV-2, circulating memory CD8 T cells rapidly extravasate to the lungs and promote expeditious viral clearance, by mechanisms that require CD4 T cell help; and (c) adoptively transferred splenic memory CD8 T cells traffic to the airways and promote lung SARS-CoV-2 clearance. These findings provide insights into the critical role of memory T cells in preventing severe lung disease following breakthrough infections with antibody-evasive SARS-CoV-2 variants.

Virological outcomes of various first-line ART regimens in patients harbouring HIV-1 E157Q integrase polymorphism: a multicentre retrospective study.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%-5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. METHODS: A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens. RESULTS: E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. CONCLUSIONS: The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate.

The emergence and spread of new SARS-CoV-2 variants with mutations in the spike protein, such as the XBB.1.5 and XBB.1.9.1 sublineages, raise concerns about the efficacy of current COVID-19 vaccines and therapeutic monoclonal antibodies (mAbs). In this study, none of the mAbs we tested neutralized XBB.1.9.1 or XBB.1.5, even at the highest concentration used. We also found that the bivalent mRNA vaccine could enhance humoral immunity against XBB.1.9.1, but that XBB.1.9.1 and XBB.1.5 still evaded humoral immunity induced by vaccination or infection. Moreover, the susceptibility of XBB.1.9.1 to remdesivir, molnupiravir, nirmatrelvir, and ensitrelvir was similar to that of the ancestral strain and the XBB.1.5 isolate in vitro. Finally, we found the replicative fitness of XBB.1.9.1 to be similar to that of XBB.1.5 in hamsters. Our results suggest that XBB.1.9.1 and XBB.1.5 have similar antigenicity and replicative ability, and that the currently available COVID-19 antivirals remain effective against XBB.1.9.1.

Incidence of sexually transmitted hepatitis C virus infection among men who have sex with men in Japan from 2009 to 2023.

Although the prevalence of hepatitis C virus (HCV) infection has decreased significantly with the advent of direct-acting antiviral agents, HCV is known to spread as a sexually transmitted disease among men who have sex with men (MSM), and this study aims to provide a perspective on the future prevalence of HCV in Japan. We examined incidence in two groups of MSM with HIV attending our institution in this retrospective cohort study, from 2009 to 2019 and from 2020 to May 2023 and investigated their background factors. Twenty-two cases were newly confirmed to be HCV infection in 2009-2019 and a total of 9 cases in 2020-2023, with an incidence rate of 5.04 per 1000 person-years in 2009-2019 and 5.55 per 1000 person-years in 2020-2023. All of them were diagnosed at routine outpatient visits for HIV, and few cases were considered to have symptoms of suspected hepatitis that led to a visit to the hospital and a diagnosis of HCV. Although HCV is still prevalent among MSM in Japan, it is possible that it would not have been diagnosed without testing at regular visits as in the case of people with HIV, and that the true prevalence rate among MSM, including non-HIV-infected persons, may be much higher.

Differences among epitopes recognized by neutralizing antibodies induced by SARS-CoV-2 infection or COVID-19 vaccination.

SARS-CoV-2 has gradually acquired amino acid substitutions in its S protein that reduce the potency of neutralizing antibodies, leading to decreased vaccine efficacy. Here, we attempted to obtain mutant viruses by passaging SARS-CoV-2 in the presence of plasma samples from convalescent patients or vaccinees to determine which amino acid substitutions affect the antigenicity of SARS-CoV-2. Several amino acid substitutions in the S2 region, as well as the N-terminal domain (NTD) and receptor-binding domain (RBD), affected the neutralization potency of plasma samples collected from vaccinees, indicating that amino acid substitutions in the S2 region as well as those in the NTD and RBD affect neutralization by vaccine-induced antibodies. Furthermore, the neutralizing potency of vaccinee plasma samples against mutant viruses we obtained or circulating viruses differed among individuals. These findings suggest that genetic backgrounds of vaccinees influence the recognition of neutralizing epitopes.

Research article antibody induction and immune response in nasal cavity by third dose of SARS-CoV-2 mRNA vaccination.

BACKGROUND: The mucosa serves as the first defence against pathogens and facilitates the surveillance and elimination of symbiotic bacteria by mucosal immunity. Recently, the mRNA vaccine against SARS-CoV-2 has been demonstrated to induce secretory antibodies in the oral and nasal cavities in addition to a systemic immune response. However, the mechanism of induced immune stimulation effect on mucosal immunity and commensal bacteria profile remains unclear. METHODS: Here, we longitudinally analysed the changing nasal microbiota and both systemic and nasal immune response upon SARS-CoV-2 mRNA vaccination, and evaluated how mRNA vaccination influenced nasal microbiota in 18 healthy participants who had received the third BNT162b. RESULTS: The nasal S-RBD IgG level correlated significantly with plasma IgG levels until 1 month and the levels were sustained for 3 months post-vaccination. In contrast, nasal S-RBD IgA induction peaked at 1 month, albeit slightly, and correlated only with plasma IgA, but the induction level decreased markedly at 3 months post-vaccination. 16 S rRNA sequencing of the nasal microbiota post-vaccination revealed not an overall change, but a decrease in certain opportunistic bacteria, mainly Fusobacterium. The decrease in these bacteria was more pronounced in those who exhibited nasal S-RBD IgA induction, and those with higher S-RBD IgA induction had lower relative amounts of potentially pathogenic bacteria such as Pseudomonas pre-vaccination. In addition, plasma and mucosal S-RBD IgG levels correlated with decreased commensal pathogens such as Finegoldia. CONCLUSIONS: These findings suggest that the third dose of SARS-CoV-2 mRNA vaccination induced S-RBD antibodies in the nasal mucosa and may have stimulated mucosal immunity against opportunistic bacterial pathogens. This effect, albeit probably secondary, may be considered one of the benefits of mRNA vaccination. Furthermore, our data suggest that a cooperative function of mucosal and systemic immunity in the reduction of bacteria and provides a better understanding of the symbiotic relationship between the host and bacteria in the nasal mucosa.

Association of demographics, HCV co-infection, HIV-1 subtypes and genetic clustering with late HIV diagnosis: a retrospective analysis from the Japanese Drug Resistance HIV-1 Surveillance Network.

INTRODUCTION: Late diagnosis of the human immunodeficiency virus (HIV) is a major concern epidemiologically, socially and for national healthcare systems. Although the association of certain demographics with late HIV diagnosis has been reported in several studies, the association of other factors, including clinical and phylogenetic factors, remains unclear. In the present study, we conducted a nationwide analysis to explore the association of demographics, clinical factors, HIV-1 subtypes/circulating recombinant form (CRFs) and genetic clustering with late HIV diagnosis in Japan, where new infections mainly occur among young men who have sex with men (MSM) in urban areas. METHODS: Anonymized data on demographics, clinical factors and HIV genetic sequences from 39.8% of people newly diagnosed with HIV in Japan were collected by the Japanese Drug Resistance HIV-1 Surveillance Network from 2003 to 2019. Factors associated with late HIV diagnosis (defined as HIV diagnosis with a CD4 count <350 cells/µl) were identified using logistic regression. Clusters were identified by HIV-TRACE with a genetic distance threshold of 1.5%. RESULTS: Of the 9422 people newly diagnosed with HIV enrolled in the surveillance network between 2003 and 2019, 7752 individuals with available CD4 count at diagnosis were included. Late HIV diagnosis was observed in 5522 (71.2%) participants. The overall median CD4 count at diagnosis was 221 (IQR: 62-373) cells/µl. Variables independently associated with late HIV diagnosis included age (adjusted odds ratio [aOR] 2.21, 95% CI 1.88-2.59, ≥45 vs. ≤29 years), heterosexual transmission (aOR 1.34, 95% CI 1.11-1.62, vs. MSM), living outside of Tokyo (aOR 1.18, 95% CI 1.05-1.32), hepatitis C virus (HCV) co-infection (aOR 1.42, 95% CI 1.01-1.98) and not belonging to a cluster (aOR 1.30, 95% CI 1.12-1.51). CRF07_BC (aOR 0.34, 95% CI 0.18-0.65, vs. subtype B) was negatively associated with late HIV diagnosis. CONCLUSIONS: In addition to demographic factors, HCV co-infection, HIV-1 subtypes/CRFs and not belonging to a cluster were independently associated with late HIV diagnosis in Japan. These results imply the need for public health programmes aimed at the general population, including but not limited to key populations, to encourage HIV testing.