HTLV Flashcards
What are the main diseases associated with HTLV-1?
Adult T-cell leukemia/Lymphoma (ATL) and HTLV-1 associated myelopathy (HAM/TSP)
ATL occurs in ~5% of all infected individuals, while HAM/TSP affects 0.25-3.8% of infected individuals.
What is the primary mechanism of disease development in HTLV-1?
Interaction between viral and host proteins leading to T-cell proliferation and transformation
This oncogenic process is particularly relevant in the case of Adult T-cell leukemia/Lymphoma (ATL).
What is the estimated global prevalence of HTLV-1 infection?
At least 5-10 million people
Prevalence data is not available for many countries, leading to potential underestimation.
In which regions is HTLV-1 endemic?
- Caribbean
- South America
- Much of Africa
- Indigenous population of Australia
- Melanesia (Fiji, PNG, Solomon Islands)
- Romania
- Iran
- Japan
What is the estimated prevalence of HTLV-1 infection among UK blood donors?
5 per 100,000 first and repeat donors
This rate has remained stable over the last 30 years.
What is the prevalence of HTLV-1 in the Antenatal setting?
50 per 100,000
This indicates a higher prevalence compared to the general UK population.
What is the prevalence of HTLV-1 in sexual health settings?
As high as 800 per 100,000
Limited evidence suggests this elevated prevalence in sexual health contexts.
What is the structure of the HTLV-1 virion?
Enveloped spherical virion (100nm) with a ssRNA genome
HTLV-1 belongs to the Retroviridae family and the Delta-retrovirinae genus.
How many subtypes of HTLV-1 are there?
Seven subtypes
Each subtype has a unique geographic distribution influenced by population migration.
Which HTLV-1 subtype is the most globally widespread?
Cosmopolitan subtype A
Subtype A has several subgroups, including transcontinental, Japanese, West and North African, Senegalese, and Afro-Peruvian.
What is the predominant subtype of HTLV-1 in Australia and Oceania?
Subtype C
This subtype is localized to distinct regions in Australia and Oceania.
What type of cell does HTLV-1 primarily infect?
CD4-T cells and ?CD8 cella
Infection occurs primarily through direct cell-to-cell contact.
How are new HTLV-1 infections typically acquired?
Transfer of infected lymphocytes
Viral RNA is NOT found in the plasma; thus, cell-free particles are not the usual source of new infections.
What receptor does HTLV-1 use to enter target cells?
GLUT1
Neuropilin-1
Heparan sulphate protoglycans
GLUT1 is a glucose transporter on target cells that mediates entry of the virus.
What happens to HTLV-1 RNA after it enters a cell?
It is reverse transcribed into DNA and integrates into the host genome as a provirus
This integration leads to lifelong infection with a long latent period before disease manifestation.
What are the main routes of HTLV-1 transmission?
M to C (mainly BF, in-utero, giving birth),
Sex,
IVDU,
Blood transfusion and Organ transplantation, Occupational exposure,
Certain cultural and religious practices (flagellation)
What is the risk associated with exclusive breastfeeding for infants with HTLV-1?
Very minimal risk for the first 3 months; thereafter, some risk
Mothers should have monitored blood and breast milk proviral load.
What is the chance of developing adult T-cell leukemia (ATL) from early life HTLV-1 infection?
1 in 5 chance
This is one of the arguments for antenatal screening.
Early life infection is key to the development of adult T-cell leukaemia
What clinical conditions are associated with HTLV-1?
ATL,
HAM/TSP,
Uveitis,
Bronchectasis,
Infective dermatitis,
Arthritis,
Peripheral neuropathy,
Disseminated Strongyloidiasis
Unexplained 57% increase in the adjusted MR
What are the clinical features of ATL?
Generalised lymphadenopathy,
Hepato-splenomegaly,
Bone and skin lesions,
Immunosuppression,
Hypercalcemia
The acute and lymphoma forms of ATL are the most aggressive.
What is the prognosis for patients with HAM/TSP?
Prognosis variable, extremely poor quality of life
Substantial proportion of patients may not be able to walk unaided 10 years after onset–> 50% wheelchair
True or False: The risk of sexual transmission of HTLV-1 is greater from females to males.
False
Risk is greater from males to females.
What is the treatment for Strongyloidiasis linked to HTLV-1 infection?
Ivermectin (2 days treatment repeated after 2 weeks)
No need to repeat serology for one year.
What immunological effect does HTLV-1 have on T-helper cells?
Activates Th1 cells, leading to overproduction of Th1-related cytokines (mainlyIFN-γandTNF-α)
## Footnote
This results in suppression of Th2 lymphocytes and reduced Th2 cytokine production (mainlyIL-4,IL-5,IL-10andIL-13) —> reduction in the ability of the infected host to mount an adequate immune response to invading organisms that require a predominantly Th2-dependent response (these include parasitic infections and the production of mucosal and humoral antibodies)
Fill in the blank: HTLV-1 has an _______ effect which becomes _______.
immunostimulating, immunosuppressive
This is a key difference from HIV.
What is the relationship between proviral load and mortality rate in HTLV-1 infected individuals?
Stronger suspicion of a relationship but not fully understood
Particularly in relation to the 57% increase in all-cause adjusted mortality rate.
What are some common symptoms of HAM/TSP?
Progressive weakness and spasticity of both legs
Incontinence
impotence
Substantial proportion will not be able to walk unaided within 10 years.
What test confirms a reactive HTLV Ab in blood?
Western Blot or Line assay
These tests also type the infection.
What is performed if serology for HTLV is inconclusive?
PCR for proviral DNA
Whole blood is required to allow extraction of DNA from lymphocytes.
Is treatment indicated for all patients with HTLV?
Not indicated if no clinical condition
However, all patients are recommended to attend specialist services.
Why it is recommendations for ALL patients with HTLV to regularly attend clinic ?
- Promptly identify onset of symptoms
- Access to clinical trials if treatment is required
- Seek advice on preventing transmission
Preventive measures include no breastfeeding, using condoms, and not donating blood.
What screening is offered to newly diagnosed HTLV patients?
Screening for associated diseases, such as strongyloidiasis
What types of ARV have activity against HTLV-1?
- NRTI
- Integrase inhibitors (INSIT)
They have been tested in clinical trials BUT do not reduce proviral DNA levels.
Which ARV classes have no anti-HTLV activity?
- NNRTI
- Protease inhibitors (PI)
What is the treatment for ATL?
- Chemotherapy
- Monoclonal antibodies (mAb)
- Bone marrow transplant (BMT)
Treatment outcomes are often poor.
What is the median life expectancy following presentation of ATL?
8-10 months
What is the first-line treatment for AT leukemia?
- AZT
- Interferon-alpha
What is important for prophylaxis in HTLV patients?
Prophylaxis against opportunistic infections
What is Mogamulizumab?
A humanized anti-CCR4 antibody
It targets CD4+ and CD8+ T cells infected with HTLV-1 and enhances anti-tumor immunity.
What conditions is Mogamulizumab used to treat?
- Relapsed/refractory CCR4-positive aggressive ATL
- May be effective against HAM-TSP
What treatments may slow progression of HAM?
- Corticosteroids
- Steroid-sparing anti-inflammatory agents
Mogamulizumab (MOG) phase 1-2a study in Japan evaluated MOG for the treatment of HAM/TSP and reported decreases in HTLV-1 proviral load and neuroinflammatory markers, with clinical improvement in some participants
What have international recommendations recently focused on?
Management of ATL and HAM
What is the status of treatment availability for conditions caused by HTLV?
Better treatments are urgently needed
General recommendations beyond the management of HAM and ATL cannot yet be made.
What is considered a significant occupational exposure to HTLV-1?
Exposure to cellular fluid (whole blood) of an HTLV-infected patient through NSI particularly when the pVL DNA is high
What is recommended for individuals with significant occupational exposure to HTLV-1?
PEP with RTG + AZT + 3TC for 6 weeks
In which populations is HTLV-2 mainly found?
Indigenous Americans and Western Africa
How does the prevalence of HTLV-2 compare to HTLV-1 in the UK?
Less common than HTLV-1
What is the association of HTLV-2 with disease?
Less frequently associated with disease; if occurs, it’s milder
What is known about HTLV-2 in disease?
Little information available
What organization coordinates national HTLV surveillance activities?
PHE
From where are LAB reports of NEW HTLV diagnoses received?
VRD: the Virus Reference Department/Colindale –. where confirm ALL HTLV diagnosis in England & Wales.
How often is clinical data on new HTLV diagnoses received?
Annually
Which centers provide specialist care for HTLV diagnoses?
Imperial College, Birmingham, York, Manchester
These centers are key providers of specialist care related to HTLV.
What additional data is collected related to HTLV diagnoses?
HTLV diagnosis data for NHSBT
NHSBT stands for National Health Service Blood and Transplant.
What did the WHO launch on 17 March 2021 regarding HTLV-1?
A technical report recognizing the unknown risk of nosocomial infection and the association of pro-viral load with transmission
The report emphasizes that further research on these issues is prioritized.
What should be considered for HTLV-1 control and prevention?
Infection control in health care settings and harm reduction for PWID
What is the current prevalence of HTLV-1 among UK healthcare workers?
Currently unknown but likely to be low
The burden of infection and risk of onward transmission to patients is also considered unlikely to be higher than in the general UK population.
Is there evidence of HTLV-1 transmission from healthcare workers to patients during an EPP?
No evidence in the literature
The risk in this context remains unknown and is limited to a small number of circumstantial case reports.
What is the assumption regarding the risk of transmission and seroconversion with low VL in donor HCWs?
The risk will be lower
This is based on expert opinion and knowledge from transmission dynamics of other viruses.
How early does the VL stabilize after HTLV-1 acquisition?
Certainly within 6 months
One cohort study showed that pVL remained stable over an 8-year period.
What are ‘Elite controllers’ in the context of HTLV-1?
Individuals with an undetectable pVL
The natural history of infection and transmission risk in this cohort has not been studied.
What is considered a high pVL cut-off for HTLV-1?
> 4% (4 HTLV-1 DNA copies per 100 peripheral blood mononuclear cells)
This level is associated with an increased risk of disease, especially ATL.
Are patients with HAM/ATL more likely to have higher pVL than those without?
Yes
The median pVL in asymptomatic carriers is 1.5%, but some may have pVL similar to those with HTLV-1 associated diseases.
Is there a curative treatment for HTLV-1 infection?
No curative treatment available
Transmission events will result in lifelong infection, and patients are monitored for sequelae such as ATL and HAM.
What is the impact of HTLV-1 transmission from HCW to patient?
Likely significant with associated risk of lifelong infection, increased morbidity and mortality
There are no curative treatments available.
Is there research available on the effectiveness of existing standard IPC in preventing HTLV-1 transmission in healthcare settings?
No research available
Applying knowledge from other BBV suggests that standard PPE and safe disposal of sharps will minimize transmission likelihood.
What risk do EPPs carry in terms of HTLV-1 transmission?
Additional risk of injury and exposure of the patient’s open tissues to the blood of theHCW, in addition to what is mitigated by standard precautions.
***EPPstherefore present a theoretically higher chance of exposure but this is NOT studied.
What is the recommendation regarding health clearance for HTLV-1 for EPP-performing HCWs?
Health clearance for HTLV-1 should NOT be introduced at this time
What are the reasons for not introducing health clearance for HTLV-1 in HCWs?
- Lack of evidence of prevalence among EPP-performing HCWs
- Unknown risk of transmission to patients
- Lack of treatment/monitoring criteria for HCWs post-diagnosis
- Deemed not proportionate/appropriate OH intervention
What does UKAP note about high VL carriers and ATL/HAM?
The majority of high VL carriers DO NOT have either condition or do not develop such conditions until years later
What percentage of HTLV infections are undiagnosed in England?
90%
SO ,, it is unreasonable to assume that aHCWwould be tested forHTLVas a consequence of such a diagnosis.
Does UKAP currently advise any restrictions from EPP practice for HCWs with known HTLV-1 infection?
No, UKAP does NOT currently advise any restrictions
HCWs should disclose their HTLV-1 status for risk assessment OH and ethical duties).
What should OH consider recording for HCWs with HTLV-1? and why?
The HCWs pVL
To inform any future risk assessments.
What is the rationale for not restricting EPP practice for HCWs with HTLV-1?
- Lack of evidence that restrictions improve patient safety
- Unknown risk of transmission via EPP
- Insufficient evidence of high VL prevalence among HCWs
- No cut-off level for safe practice can be established
Does UKAP recommend routine occupational health monitoring of HCWs infected with HTLV-1?
No, UKAP does not currently recommend routine monitoring
Due to lack of evidence regarding transmission risk and high VL likelihood.
What should be done in case of patient exposure to HCWs infected with HTLV-1?
Seek advice from a local virologist, local HPT, and national experts on HTLV on a case-by-case basis
A risk assessment may also be considered.
Why is it important to contact virology or national experts urgently after patient exposure?
To determine whether the exposed patient requires PEP (Post-Exposure Prophylaxis)
The administration of PEP is time-limited.
What is the primary purpose of the HTLV DNA qPCR test?
HTLV-I DNA viral load measurement for diagnosis and monitoring of disease in patients infected with HTLV-1 and HTLV-2.
What method is used to measure HTLV-1/2 viral load?
An in-house method using real-time quantitative PCR monitored by SYBR Green I dye incorporation.
Which genes are targeted by primers in the HTLV DNA qPCR test?
HTLV-1 and HTLV-2 Tax gene.
How is HTLV-1/2 copy number expressed in the test results?
As HTLV-1/2 DNA copies per 100 PBMCs.
What is the next step if extracted DNA has an appropriate β-globin gene copy number but NO quantifiable HTLV-1/2 DNA?
A PCR is carried out using nested primers specific for HTLV-1 or HTLV-2.
What is the purpose of the HTLV typing by PCR test?
To discriminate between HTLV-1 and HTLV-2 infection.
What is the procedure for HTLV typing by PCR?
PCR amplification of the tax gene sequence of HTLV DNA extracted from PBMCs using generic outer primers in the first round and discriminatory inner primers in the second round.
How are PCR products detected in HTLV typing?
PCR products are detected on an agarose gel.
What controls are run in parallel during HTLV typing?
HTLV-1, HTLV-2, and negative controls.
What is the turnaround time for issuing reports for proviral load?
Within two weeks of receiving a sample.
What is the turnaround time for genotyping reports?
Within four weeks of receiving a sample.
What types of samples are suitable for the HTLV tests?
Whole EDTA blood,
CSF, and
Fresh tissue/shavings from paraffin-embedded blocks.
What should not be sent as a sample for HTLV testing?
Plasma.
