Accurate detection of copy number aberrations in FFPE samples using the mFAST-SeqS approach.

BACKGROUND: Shallow whole genome sequencing (Shallow-seq) is used to determine the copy number aberrations (CNA) in tissue samples and circulating tumor DNA. However, costs of NGS and challenges of small biopsies ask for an alternative to the untargeted NGS approaches. The mFAST-SeqS approach, relying on LINE-1 repeat amplification, showed a good correlation with Shallow-seq to detect CNA in blood samples. In the present study, we evaluated whether mFAST-SeqS is suitable to assess CNA in small formalin-fixed paraffin-embedded (FFPE) tissue specimens, using vulva and anal HPV-related lesions. METHODS: Seventy-two FFPE samples, including 36 control samples (19 vulva;17 anal) for threshold setting and 36 samples (24 vulva; 12 anal) for clinical evaluation, were analyzed by mFAST-SeqS. CNA in vulva and anal lesions were determined by calculating genome-wide and chromosome arm-specific z-scores in comparison with the respective control samples. Sixteen samples were also analyzed with the conventional Shallow-seq approach. RESULTS: Genome-wide z-scores increased with the severity of disease, with highest values being found in cancers. In vulva samples median and inter quartile ranges [IQR] were 1[0-2] in normal tissues (n = 4), 3[1-7] in premalignant lesions (n = 9) and 21[13-48] in cancers (n = 10). In anal samples, median [IQR] were 0[0-1] in normal tissues (n = 4), 14[6-38] in premalignant lesions (n = 4) and 18[9-31] in cancers (n = 4). At threshold 4, all controls were CNA negative, while 8/13 premalignant lesions and 12/14 cancers were CNA positive. CNA captured by mFAST-SeqS were mostly also found by Shallow-seq. CONCLUSION: mFAST-SeqS is easy to perform, requires less DNA and less sequencing reads reducing costs, thereby providing a good alternative for Shallow-seq to determine CNA in small FFPE samples.

Neutralization Heterogeneity of UK and South African Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in BNT162b2-Vaccinated or Convalescent Coronavirus Disease 2019 (COVID-19) Healthcare Workers.

There are concerns about neutralizing antibodies' (NAbs') potency against severe acute respiratory syndrome coronavirus 2 variants. Despite decreased NAb titers elicited by BNT162b2 vaccine against VOC202012/01 and 501Y.V2 strains, 28/29 healthcare workers (HCWs) had an NAb titer ≥1:10. In contrast, 6 months after coronavirus disease 2019 mild forms, only 9/15 (60%) of HCWs displayed detectable NAbs against 501Y.V2 strain.

Human Herpesvirus 8 seroprevalence among blood donors in Mali.

In sub-Saharan Africa, the Human Herpesvirus 8 (HHV-8) is endemic but with disparities between regions and population studied. Although the virus remains mostly latent, there is some evidence that blood transfusion may represents one of the transmission way for this virus. Here, we evaluated HHV-8 seroprevalence among blood donors in Mali. This cross-sectional study recruited blood donors from the Blood Transfusion Center at Gabriel Touré Hospital, Bamako. Serum was used for the detection of latent HHV-8 immunoglobulin G directed against latent associated nuclear antigen 1 by an indirect immunofluorescence assay. Human immunodeficiency virus 1 (HIV-1), Hepatitis B Virus (HBV), HCV, and Treponema pallidum were also screened. HHV-8 seroprevalence was 10.4% in Malian blood donors. None of the sociodemographic characteristics were associated with HHV-8 infection, although there is a tendency of a higher HHV-8 seroprevalence among participants living in Bamako than those not living there. One individual had coinfection HHV-8/HBV, another HHV-8/HCV while another had HCV and T. pallidum. None has been tested positive for HIV infection. This intermediate seroprevalence in Malian blood donors suggests that the risk of HHV-8 transmission by transfusion should be considered. Further investigations are needed to assess impact of HHV-8 in polytransfused patients residing in an endemic area for this virus.

Emerging RNA-Dependent RNA Polymerase Mutation in a Remdesivir-Treated B-cell Immunodeficient Patient With Protracted Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered virus for which remdesivir is the only antiviral available. We report the occurrence of a mutation in RdRP (D484Y) following treatment with remdesivir in a 76-year-old female with post-rituximab B-cell immunodeficiency and persistent SARS-CoV-2 viremia. A cure was achieved after supplementation with convalescent plasma.

Presence of HIV-1 G-to-A mutations linked to APOBEC editing is more prevalent in non-B HIV-1 subtypes and is associated with lower HIV-1 reservoir.

OBJECTIVES: APOBEC3 editing activity contributes to sequences variation and viral diversification. We aimed to characterize virological and clinical factors associated with G-to-A mutations and stop codons in the HIV-1 reservoir, markers of APOBEC3 footprints, in order to better understand HIV-1 diversity among virologically suppressed HIV-1-infected patients. METHODS: Immuno-virological and clinical factors were compared between 92 patients harbouring G-to-A mutations and stop codons (APOBEC+) in the reverse transcriptase gene and 92 patients without G-to-A mutations (APOBEC-) and stop codons in their DNA genotypes. RESULTS: Patients were predominantly men (74.5%) and were mostly infected by B-subtype (69.0%), with 44.1% and 55.9% in APOBEC+ and APOBEC- groups, respectively. At time of HIV DNA genotypes, the total cell-associated HIV-1 DNA load was 2.34 log10 copies/106 cells (IQR 1.85-2.67) and 33.2% of them had a detectable ultrasensitive plasma viral load. Hypermutated sequences were identified in 28.2% of the APOBEC+ group. The median total cell-associated HIV-1 DNA level was significantly lower in APOBEC+ than APOBEC- group: 2.13 log10 copies/106 cells (IQR 1.60-2.60) versus 2.52 log10 copies/106 cells (IQR 2.19-2.71) (P < 0.001), respectively. Presence of G-to-A mutations and stop codon was independently associated with HIV-1 subtype non-B (P = 0.017). CONCLUSIONS: These results show an independent association between the presence of G-to-A mutations and stop codons with HIV-1 subtype non-B and low proviral DNA that could be explained by the APOBEC3 footprints and restriction of DNA synthesis and integration. However, further investigations are needed to study the contribution of Vif amino acid variability among HIV-1 subtypes.

A community-based healthcare package combining testing and prevention tools, including pre-exposure prophylaxis (PrEP), immediate HIV treatment, management of hepatitis B virus, and sexual and reproductive health (SRH), targeting female sex workers (FSWs) in Côte d'Ivoire: the ANRS 12381 PRINCESSE project.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is recommended by the WHO for HIV prevention among female sex workers (FSWs). A study conducted in 2016-2017 in Côte d'Ivoire showed that if PrEP is acceptable, FSWs also have many uncovered sexual health needs. Based on this evidence, the ANRS 12381 PRINCESSE project was developed in collaboration with a community-based organization. The main objective is to develop, document, and analyze a comprehensive sexual and reproductive healthcare package among FSWs in Côte d'Ivoire. METHODS: PRINCESSE is an open, single-arm interventional cohort of 500 FSWs in San Pedro (Côte d'Ivoire) and its surroundings. Recruitment started on November 26th, 2019 and is ongoing; the cohort is planned to last at least 30 months. The healthcare package (including HIV, hepatitis B, and sexually transmitted infection management, pregnancy screening, and contraception) is available both at mobile clinics organized for a quarterly follow-up (10 intervention sites, each site being visited every two weeks) and at a fixed clinic. Four waves of data collection were implemented: (i) clinical and safety data; (ii) socio-behavioral questionnaires; (iii) biological data; and (iv) in-depth interviews with female participants. Four additional waves of data collection are scheduled outside the cohort itself: (i) the medical and activity records of Aprosam for the PRINCESSE participants; (ii) the medical records of HIV+ FSW patients not participating in the PRINCESSE cohort, and routinely examined by Aprosam; (iii) in-depth interviews with key informants in the FSW community; and (iv) in-depth interviews with PRINCESSE follow-up actors. DISCUSSION: The PRINCESSE project is one of the first interventions offering HIV oral PrEP as part of a more global sexual healthcare package targeting both HIV- and HIV+ women. Second, STIs and viral hepatitis B care were offered to all participants, regardless of their willingness to use PrEP. Another innovation is the implementation of mobile clinics for chronic/quarterly care. In terms of research, PRINCESSE is a comprehensive, interdisciplinary project combining clinical, biological, epidemiological, and social specific objectives and outcomes to document the operational challenges of a multidisease program in real-life conditions. TRIAL REGISTRATION: The PRINCESSE project was registered on the Clinicaltrial.gov website ( NCT03985085 ) on June 13, 2019.

New Kaposi's sarcoma-associated herpesvirus variant in men who have sex with men associated with severe pathologies.

BACKGROUND: Kaposi sarcoma (KS)-associated herpesvirus (KSHV) subtype depends mostly on patient origin. The current study aimed to assess KSHV diversity in a population of men who have sex with men (MSM) living in France. METHODS: The study included 264 patients. In 65 MSM, including 57 human immunodeficiency virus (HIV)-infected men with KS, multicentric Castleman disease, or primary effusion lymphoma and 8 HIV-uninfected men receiving HIV preexposure prophylaxis (PrEP), we performed KSHV typing with K1 open reading frame Sanger and KSHV whole-genome sequencing. In 199 other patients, we performed real-time polymerase chain reaction screening for the new variant. RESULTS: We found that 51% of KSHV-strains were subtype C (85% C3), and 33% were subtype A. Four patients with severe KSHV disease (2 with visceral KS, 1 with multicentric Castleman disease, and 1 with primary effusion lymphoma) and 1 asymptomatic PrEP user had a new variant resembling the Ugandan subtype F, but with different K1 open reading frame and KSHV whole-genome sequences and a different epidemiological context (MSM vs African population). Its prevalence was 4.5% in Caucasian MSM, and it was absent in other epidemiological groups. CONCLUSIONS: Subtype C predominated among MSM living in France. The new F variant was identified in Caucasian MSM and associated with severe KSHV disease, suggesting that subtype F could be split into F1 and F2 variants. Careful screening for this variant may be required in MSM, given the severe clinical presentation of associated diseases.

Recurrence and Occurrence of Kaposi's Sarcoma in Patients Living With Human Immunodeficiency Virus (HIV) and on Antiretroviral Therapy, Despite Suppressed HIV Viremia.

In 21 cutaneous and/or visceral Kaposi's sarcoma cases, occurring in patients living with human immunodeficiency virus (HIV) who were on antiretroviral therapy with suppressed HIV viremia and high CD4 T cell counts, the efficacy of conventional chemotherapies was limited due to cumulative toxicities, comedications, and a lack of immune improvement.

Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients.

BACKGROUND: GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207. OBJECTIVES: To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH). METHODS: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N. RESULTS: Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history. CONCLUSIONS: Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations.

M184V/I does not impact the efficacy of abacavir/lamivudine/dolutegravir use as switch therapy in virologically suppressed patients.

BACKGROUND: M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I. OBJECTIVES: We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors. PATIENTS AND METHODS: A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50 copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12 months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia. RESULTS: During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL <50 copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up. CONCLUSIONS: M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months.

Prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients from two large databases in France and Italy.

OBJECTIVES: Doravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients. METHODS: Doravirine-associated resistance mutations identified in vitro or in vivo were studied in a set of 9199 HIV-1 RT sequences from HIV-1 antiretroviral-experienced patients, including 381 NNRTI-failing patients in France and Italy between 2012 and 2017. The following mutations were considered as resistance mutations: V106A/M, V108I, Y188L, G190S, F227C/L/V, M230I/L, L234I, P236L, K103N + Y181C, K103N + P225H and K103N + L100I. RESULTS: The frequencies of doravirine-associated resistance mutations (total dataset versus NNRTI-failing patients) were: V106A/M, 0.8% versus 2.6%; V108I, 3.3% versus 9.2%; Y188L, 1.2% versus 2.6%; G190S, 0.3% versus 2.1%; F227C/L/V, 0.5% versus 1.8%; M230I/L, 2.8% versus 0%; L234I, 0.1% versus 0.5%; K103N + Y181C, 3.9% versus 3.9%; K103N + P225H, 2.9% versus 4.7%; and K103N + L100I, 1.7% versus 3.9%, with a significantly higher proportion of these mutations in the NNRTI-failing group (P < 0.05), except for M230I/L and K103N + Y181C. The overall prevalence of sequences with at least one doravirine-associated resistance mutation was 12.2% and 34.9% in the total dataset and NNRTI-failing patients (P < 0.001), respectively. In comparison, the prevalence of the common NNRTI mutations V90I, K101E/P, K103N/S, E138A/G/K/Q/R/S, Y181C/I/V and G190A/E/S/Q were higher (8.9%, 7.9%, 28.6%, 12.6%, 14.2% and 8.9%, respectively). CONCLUSIONS: These results suggest that doravirine resistance in antiretroviral-experienced patients generally and specifically among NNRTI-failing patients is lower than resistance to other NNRTIs currently used, confirming its distinguishing resistance pattern.

Seroprevalence and risk factors for HIV, HCV, HBV and syphilis among blood donors in Mali.

BACKGROUND: HIV, HBV and HCV remain a global public health concern especially in Africa. Prevalence of these infections is changing and identification of risk factors associated with each infection in Mali is needed to improve medical care. METHODS: We conducted a cross-sectional study of all individuals donating blood (n = 8207) in 2018 to the blood bank at university hospital in Bamako, Mali, to assess prevalence and risks factors associated with HIV, HBV, HCV and syphilis infections. RESULTS: HIV-seroprevalence was 2.16% and significantly increased with age, being married and decreasing education level. In multivariate analysis, after adjustements with age, marital status and geographical setting, only education level was associated with HIV-infection (OR, 1.54 [95% CI, 1.15-2.07], p = 0.016). HBsAg prevalence was 14.78% and significantly increased with to be male gender. In multivariate analysis, adjusting for age, marital status and type of blood donation, education level (OR, 1.17 [95%CI, 1.05-1.31], p = 0.02) and male gender (OR, 1.37 [95%CI, 1.14-1.65], p = 0.005) were associated with HBV-infection. HCV-prevalence was 2.32% and significantly increased with living outside Bamako. In multivariate analysis, adjusting for gender, age and education level, living outside Bamako was associated with HCV-infection (OR, 1.83 [95% CI, 1.41-2.35], p < 0.001). Syphilis seroprevalence was very low (0.04%) with only 3 individuals infected. Contrary to a prior study, blood donation type was not, after adjustments, an independent risk factor for each infection. CONCLUSIONS: Overall, HIV and HBV infection was higher in individuals with a lower level of education, HBV infection was higher in men, and HCV infection was higher in people living outside of Bamako. Compared to studies performed in 1999, 2002 and 2007 in the same population, we found that HIV and HCV prevalence have decreased in the last two decades whereas HBV prevalence has remained stable. Our finding will help guide infection prevention and treatment programs in Mali.

Similar Viral and Immune Characteristics of Kaposi Sarcoma in ART-treated People Living With HIV and Older Patients With Classic Kaposi Sarcoma.

Background: Reemergence of human herpesvirus 8 (HHV-8)-induced Kaposi sarcoma (KS) in people living with HIV (PLWH) despite antiretroviral therapy (ART) poses a clinical challenge because they already have favorable CD4 T-cell numbers and undetectable viral loads. We observed that clinical presentation in PLWH on ART resembled classic KS found in older HIV-uninfected patients and hypothesized that immunosenescence may thus play a role in occurrence of KS on ART. We compared viral and immune factors implicated in the development of KS in ART-treated PLWH (HIV KS) and HIV-uninfected classic KS patients (cKS), compared to controls without KS (HIV Control, cControls respectively). Methods: Plasma, peripheral blood mononuclear cell, and skin tissues were obtained from 11 HIV KS and 11 cKS patients and 2 groups of age-matched controls. Results: HIV KS participants were younger than cKS (aged 53 vs 75 years). HHV-8 genotypes did not differ between groups. Despite the younger age and a lower CD4/CD8 ratio, activated, exhausted, and senescent T-cell frequencies were similar between HIV KS and cKS. Anti-HHV-8 immunoglobulin G levels were higher and circulating HHV-8 DNA lower in HIV KS compared with cKS. Circulating platelet-derived growth factors AA-BB and granulocyte colony-stimulating factors were higher in HIV KS We observed similar levels of HHV-8 DNA and PD-1 expression in skin lesions from HIV KS and cKS patients. Conclusions: Altogether, early immune senescence could be involved in the development of KS in ART-treated PLWH. Higher anti-HHV-8 immunoglobulin G levels could be linked with lower circulating viral load. Such insights should help developing therapeutical strategies to prevent development and treat KS in PLWH on ART.

Comparative Performance of Anyplex II HPV28 and Cobas 4800 Human Papillomavirus (HPV) Assays for High-Risk HPV Detection in Self-collected Anal Samples.

We compared 2 human papillomavirus (HPV) assays to detect the 14 high-risk HPV (hrHPV) genotypes in self-collected anal samples. We found a good agreement and similar performance to detect HPV-16, HPV-18, and the 12 other hrHPV genotypes. The global performance to detect the 14 hrHPV genotypes was not significantly different between the 2 assays.

Enhanced fetal hematopoiesis in response to symptomatic SARS-CoV-2 infection during pregnancy.

BACKGROUND: Pregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation. METHODS: We studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2. RESULTS: Here we show that symptomatic maternal COVID-19 is associated with a transcriptional erythroid cell signature as compared with asymptomatic and uninfected mothers. We observe an expansion of fetal hematopoietic multipotent progenitors skewed towards erythroid differentiation that display increased clonogenicity. There was no difference in inflammatory cytokines levels in the cord blood upon maternal SARS-CoV-2 infection. Interestingly, we show an activation of hypoxia pathway in cord blood cells from symptomatic COVID-19 mothers, suggesting that maternal hypoxia may be triggering this fetal stress hematopoiesis. CONCLUSIONS: Overall, these results show a fetal hematopoietic response to symptomatic COVID-19 in pregnant mothers in the absence of vertically transmitted SARS-CoV-2 infection which is likely to be a mechanism of fetal adaptation to the maternal infection and reduced oxygen supply.

During pregnancy, women are more prone to respiratory infectious diseases. It is not known if COVID-19 infection has an adverse effect on the growing fetus. Here, we aimed to identify any potential effects of COVID-19 infection on the fetus by taking measurements from the umbilical cord blood cells. In mothers who displayed symptomatic COVID-19 infection, we observed an increased production of hematopoietic progenitor cells, especially the ones that are responsible for producing red blood cells. We think this might be a coping mechanism for the fetus, as the mother's body deals with the infection. Therefore, our work shows that growing fetuses do respond to maternal COVID-19 symptoms, even when they are protected in the womb from the infection and may never get infected by the mother.

Phylodynamics of SARS-CoV-2 in France, Europe, and the world in 2020.

Although France was one of the most affected European countries by the COVID-19 pandemic in 2020, the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) movement within France, but also involving France in Europe and in the world, remain only partially characterized in this timeframe. Here, we analyzed GISAID deposited sequences from January 1 to December 31, 2020 (n = 638,706 sequences at the time of writing). To tackle the challenging number of sequences without the bias of analyzing a single subsample of sequences, we produced 100 subsamples of sequences and related phylogenetic trees from the whole dataset for different geographic scales (worldwide, European countries, and French administrative regions) and time periods (from January 1 to July 25, 2020, and from July 26 to December 31, 2020). We applied a maximum likelihood discrete trait phylogeographic method to date exchange events (i.e., a transition from one location to another one), to estimate the geographic spread of SARS-CoV-2 transmissions and lineages into, from and within France, Europe, and the world. The results unraveled two different patterns of exchange events between the first and second half of 2020. Throughout the year, Europe was systematically associated with most of the intercontinental exchanges. SARS-CoV-2 was mainly introduced into France from North America and Europe (mostly by Italy, Spain, the United Kingdom, Belgium, and Germany) during the first European epidemic wave. During the second wave, exchange events were limited to neighboring countries without strong intercontinental movement, but Russia widely exported the virus into Europe during the summer of 2020. France mostly exported B.1 and B.1.160 lineages, respectively, during the first and second European epidemic waves. At the level of French administrative regions, the Paris area was the main exporter during the first wave. But, for the second epidemic wave, it equally contributed to virus spread with Lyon area, the second most populated urban area after Paris in France. The main circulating lineages were similarly distributed among the French regions. To conclude, by enabling the inclusion of tens of thousands of viral sequences, this original phylodynamic method enabled us to robustly describe SARS-CoV-2 geographic spread through France, Europe, and worldwide in 2020.

Therapeutic Perspectives in the Systemic Treatment of Kaposi's Sarcoma.

In patients with Kaposi's sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects.