HIV 2 Flashcards
What are the two main types of HIV?
HIV-1 and HIV-2
HIV-1 is closely related to a SIV in chimpanzees, while HIV-2 is related to an SIV in sooty mangabeys (SIVsmm)
What are the steps of the HIV replication cycle?
1)Binding/attachment: HIV envelope GP 120 binds/attach to CD4 receptor and then interact with co-receptors chemokine CCR5 and CXCR4 (CCR5 antagonist and post-attachment inhibitors)
2)Fusion: the HIV envelope and the CD4 cell membranes fuse, which allows HIV to enter the CD4 cell (Fusion inhibitors)
3)Reverse transcription: inside the CD4 cell, HIV releases (un-coating) and uses RT to convert its genetic material (HIV RNA) into HIV cDNA, this allows HIV to enter the CD4 cell nucleus (NRTIs and NNRTIs).
4)Integration: inside the CD4 cell nucleus, HIV releases integrase which integrates the HIV cDNA into the CD4 cell DNA.
5)Replication: once integrated into the CD4 cell DNA, HIV begin to use the machinery of the CD4 cell to make long chains of HIV proteins (viral RNA and mRNA—> HIV proteins).
6)Assembly: New HIV proteins and HIV RNA move to the surface of the cell and assemble into immature (non-infection) HIV.
7)Budding: Newly formed immature (non-infectious) HIV pushes itself out of the host Cd4 cell. The new HIV releases protease which breaks up the long protein chains in the immature virus, creating the mature (infectious virus (PIs)
How does HIV-2 prevalence compare to HIV-1?
HIV-2 is much less common than HIV-1
Estimated 1–2 million people living with HIV-2 worldwide including those with dual HIV-1 and HIV-2 infection.
What is a challenge in diagnosing, monitoring and management of HIV-2?
HIV-2 groups are so distinct from each other that it is common for resistance tests, and even viral load assays, to fail to amplify which causes further delay in treatment decisions.
How does disease progression in untreated HIV-2 compare to HIV-1?
HIV-2 progresses at a slower rate than HIV-1
Most untreated individuals with HIV-2 will eventually experience disease progression
What is the most useful marker of health status in HIV-2 patients?
CD4 count
CD4 count is monitored frequently due to low/undetectable viral load
What are the important differences in natural history between HIV-1 and HIV-2?
1)HIV-2 carries a lower risk of horizontal and VT related to much lower plasma VL
2)HIV-2 plasma VL often undetectable without ART.
3)There is a slower CD4 T-cell decline but some AIDS-defining illnesses may develop at higher CD4 counts.
4)The disease trajectory of HIV-1 and HIV-2 is almost identical but progresses at approximately half the rate in HIV-2 so that a prolonged asymptomatic phase is more common.
5)Clinical disease due to HIV-2 is indistinguishable from that due to HIV-1.
6)Resistance mutations in protease and RT can develop commonly in HIV-2 as the resistance barrier is lower and their effect on treatment efficacy is less well clinically characterised than in HIV-1
7)Mortality is same as for CD4-matched people with HIV-1.
When was HIV-2 initially isolated?
1986
The first sequence was published in 1987
How many subtypes does HIV-2 have?
9 subtypes (A-I)
Only groups A and B have become endemic
What is the effect of prior infection with HIV-2 on acquisition of HIV-1 in dual infection? and why?
It delays clinical progression, compared to HIV-1 mono-infection
This dampening of the infectivity of HIV-1 was a result of inter-viral interference carried out by viral protein X of HIV-2, resulting in a severe hindrance to the replication dynamics of HIV-1, influencing both its early and late phases of the viral life cycle
What is the geographical distribution of HIV-2?
Mainly restricted to West Africa
Highest prevalence in
Guinea-Bissau,
The Gambia,
Senegal,
Cape Verde,
Côte d’Ivoire, and
Sierra Leone
Which countries in Europe have the highest prevalence of HIV-2?
Portugal and France have the highest number of PLWH-2 in Europe with approximately 2000 and 1000 people respectively.
What has been observed in studies regarding HIV-2 prevalence in recent years?
Recent rapid decrease in prevalence
Speculation exists that HIV-2 may become extinct by the middle of the 21st century
What are the suggested reasons for decreasing prevalence?
Its lower transmission risk,
Changes in risk behaviour,
Reduced risk of HCAI and/or
Competition with HIV-1.
What is the estimated time frame for species jumping into humans for HIV-2 group A?
1905-1942
Group B occurred between 1914-1945
What is a potential risk for individuals with HIV-2 regarding treatment?
Resistance may develop more easily
Treatment may need closer monitoring to minimize resistance risk
How do HIV-2 resistance mutations compare to those in HIV-1?
Resistance mutations in protease and RT can develop commonly in HIV-2
The resistance barrier is lower and less well characterized clinically
What has been noted about the health status of HIV-1 elite controllers compared to those with HIV-2?
Elite controllers have Increased risk of non-AIDS adverse events
This occurs even in the absence of detectable viraemia
What is a key recommendation for supporting PLWH-2?
-Involve pts in their care
-Providing treatment and peer support
-Adherence support due to limited treatment options.
*Switching because of intolerance to ARV is less of an option than for HIV-1
What is the ancestry of most PLWH-2 in the UK?
West African ancestry or migrated from there/From France/Portugal
This group has greater language and communication needs.
How many CE-marked serology tests are recommended for the initial diagnosis of chronic HIV-2 infection?
A total of 3 CE-marked serology tests
Tests must conform to EU health and safety requirements and be performed in an ISO 15189-accredited lab.
When is the test considered reactive for HIV-2?
Reactivity in two CE-marked 4th-generation tests for HIV-1 and HIV-2 followed by differentiation of HIV-2 by a third CE-marked antibody-ONLY test
What is required for the confirmation of HIV-2 diagnosis?
As with HIV-1, the patient identity for HIV-2 diagnosis is not confirmed UNTIL a second sample from the patient has consistent reactive results.
What are the following steps in diagnosis if the 1st test was a POCT/self-sampling test?
This is considered as one of the two samples.
Therefore, one POCT-reactive sample + one laboratory reactive sample with differentiation for HIV type is considered adequate for confirmation of identity and HIV-2 infection.
What indicates the need to revisit a previous diagnosis of HIV-1? what tests should be done?
An undetectable HIV-1 VL in the absence of ART BUT falling CD4 count
This is to detect the possibility of missed HIV-1 and HIV-2 dual infection.
Testing for HIV-2 serology and molecular tests
Under what conditions should clinicians consider repeating HIV-1 diagnostic tests in individuals diagnosed with HIV-2? and how?
An undetectable viral load in the absence of ART BUT falling CD4 count
This is to investigate the possibility of HIV-1 superinfection.
By repeating HIV-1 diagnostic tests
What is the significance of 4th generation serology tests in HIV diagnosis?
They have become the mainstay of HIV diagnosis, but the 4th gen is actually a 3rd generation test
As It only detects antibodies
What is the cumulative probability of a false-negative HIV test result for third-generation tests at 40 days?
5%
This decreases to 1% at 85 days and 0% at 99 days post-exposure.
How is Acute Primary/very recent HIV-2 infection diagnosed?
Recommend that investigations should start as for diagnosis of chronic HIV2 infection.
A negative HIV2 screening result on a blood sample taken within 3M of the likely exposure should be further investigated at 6W and 3M + parallel testing for HIV2 viral RNA, if necessary, HIV2 proviral DNA.
Diagnosis of acute primary HIV-2 infection can ONLY be made on the basis of HIV-2 Ab SEROCONVERSION.
What are the possible clinical scenarios that indicate testing for acute HIV-2 infection?
The need to test for a suspected acute HIV-2 is rare.
May be considered in following situations:
-NSI
-Sexual exposure
-Other potential transmission event
-Clinical presentation
What is the FDA-approved test for identifying acute HIV infection?
Roche cobas® HIV-1/HIV-2 qualitative RT-PCR test
This test may help in diagnosing acute infection.
What should be done if HIV-1/HIV-2 serology does not fit a clear pattern?
Recommend that any HIV-1/HIV-2 serology that does not fit into a clear pattern of a confirmed laboratory diagnosis is fully investigated for the presence/absence of HIV-2 infection, and that this should be established by PCR for HIV-2 proviral DNA.
-Because of the close genetic relationship b/w HIV1 and HIV2, reactivity in combined serological tests reflect cross-reactivity to either Ab/Ag.
-A fuller investigation of suspected cross-reactive serology shud include an HIV-2 western blot analysis (better compare the range of the pts serological response to HIV1/2 Ag) —> NOT available in the UK —> specialist confirmation of HIV-2 infection depends on molecular testing
The next step would normally be an HIV2 VL test, BUT because significant proportion of pts with HIV2 do NOT have detectable HIV2 VL—> Negative result can b misleading —> though not quantitative *** Roche Cobas HIV1/HIV2 qualitative RT-PCR test has a VERY LOW estimated LOD and may b helpful.
What is the next step if RNA is not detected in HIV-2 testing?
Test for HIV-2 proviral DNA
This test is more exacting in terms of sample requirements.
Must be sent to the lab within a short period—> because it require separating the WCC from WB
Test is Capable of reliably and specifically detecting HIV2 DNA that has been integrated into human lymphocytes.
What should be measured at baseline (BL) for people with HIV-2?
Viral load (VL) at BL and repeated at appropriate intervals.
What factors affect the viral load level in HIV-2 patients?
- Time since infection
- Clinical progression
- varies between patients
In studies in West Africa, the proportion of ART-naïve individuals with VL <50 c/mL varied b/w 25%-40%, compared with 0.15–1.5% for HIV-1
What are the benefits of checking the VL at BL?
-Allow genotype testing
-Monitor response to ART
-Monitor disease progression on those who do not start ART
**If detectable can correlate with disease progression BUT there is proportion who will progress without detectable/increasing HIV2 VL
What is the Cavidi ExaVir assay ?
-Commercial HIV VL assay
-Offers a different methodology—> measures the polymerase activity of plasma virons
-LESS sensitive than RT-PCR assays (~500 vs ~100c/ml)
-CANNOT distinguish b/w HIV1 and HIV2 load in co-infected pts
-Has shown promise in single-sample limited comparisons with RT-PCR assays
What challenge is faced in quantifying HIV-2 subtype viral load?
More problematic due to wider variation across the viral genome/natural variation in critical primer-binding sites, and
limits of both quantification and detection
This can lead to under quantification and discordance with clinical progression.
What does the BHIVA/BASHH/BIA Adult HIV testing guidelines recommend?
Use a test at a time point with a 99% probability of detecting infection
This is crucial for accurate diagnosis.
When should resistance testing for HIV-2 be performed?
At diagnosis, prior to treatment initiation, and at virological failure if the HIV-2 VL is ≥500 copies/mL.
What type of resistance testing is used for HIV-2?
Only genotypic resistance testing is used routinely; phenotypic testing is not.
Only 1 lab in the Uk accredited HIV R test
QA is provided by in-house and international schemes.
Can R test be done if VL <500c/ml? and what ARV classes are tested?
If VL is <500c/ml —> d/w specialist lab may still do the test
Testing is for PI, NRTI and ISTI
Intrinsic resistance to NNRTI and fusion inhibitor ENFUviritide
What are the basic methodology for genotypic HIV-2 resistance testing?
similar to that used for HIV-1:
-Extraction of viral RNA from plasma, then
-Reverse transcription of RNA to complementary (c)DNA, followed by
-Nested PCR amplification of specific regions of this cDNA —>checking for amplification, the product is then
-Sequenced —> scanned for quality of sequence, and
-Analysed for the presence of mutations that are predicted to confer drug resistance.
-Lists of mutations used in the scanning process are updated regularly and available from international databases and are based on peer-reviewed clinical research
What is the limit of sensitivity for point mutations in HIV-2 sequencing using Sanger methodology?
Approximately 15%.
Thus, any mutations present in a viral population at a proportion <15% are unlikely to be reliably detected, though whether these will have clinical consequences for AV control of HIV-2 infection is largely unknown.
What are the recommended circumstances for starting ART in PLWH-2?
Essential to discuss R/B of starting ART
Suggest that ALL PLWH-2 start ART.
RECOMMEND that PLWH-2 start ART in the following circumstances:
-DUAL HIV1 and HIV2 infection
-Diagnosis made during PRIMARY HIV2 infection
-Co-INFECTION with HBV
-IN PREGNANCY
-Detectable VIRAEMIA**
-CD4 <500 cells/mm3
-ADVANCED HIV disease(CD4<200 or WHO stage 3/4 clinical event at presentation)/OI (No trial evidence to when to start)
-Symptoms/indicator condition (current/previous) for HIV1 and/or HIV2 regardless of CD4/VL.
Suggest additional consideration is given to starting ART if there are significant comorbidities.
**To prevent disease progression Prevent onward transmission Reduce the risk of non-AIDS adverse events
True or False: There are randomized controlled trials (RCT) to determine the optimal timing for starting ART in HIV-2.
False.
Limiting ability to make strong recommendations based on high-quality evidence.
What does the overall evidence suggests w/r HIV-2 natural disease without ART?
HIV-2 infection will progress to AIDS, and death in the majority of individuals, with life expectancy ~10Y shorter among people with HIV-2 vs without HIV
Decline in CD4 cell count and clinical progression can occur in HIV-2 in the absence of detectable viraemia
What findings support ART initiation in PLWH-2?
-PLWH-2 were more likely to develop CLINICAL AIDS at higher CD4 cell % compared to PLWH-1 (18% vs 8%) may be partly explained by the longer periods of time spent with mild/moderate immune suppression.
-Mortality off-treatment is substantial and that disease progression is similar to but slower than in those with HIV-1.
-TasP —> It is biologically plausible and likely that the same applies to HIV-2 (U=U).
What should be assessed if immediate ART is not planned for individuals with HIV-2?
The risk of acquisition of HIV-1.
What is the recommendation for ART in individuals with dual infection of HIV-1 and HIV-2?
Start an ART regimen that provides full suppression for both viruses.
Monitoring for VF should include VL and drug resistance testing for both viruses
Apart from confirmed HIV-2 diagnosis; when it is worth considering use of a regimen active against both viruses? and Why?
Where there is diagnostic uncertainty about the possibility of dual infection/single HIV2 infection (eg an equivocal Ab test result) OR
While waiting for an HIV-2 VL result from a ref lab.
Because resistance may be more likely to develop in HIV-2 than HIV-1, and that managing VF in HIV-2 is a challenge due to limited treatment options
What are the benefits of initiating ART in primary HIV-2 infection? based on what evidence?
-Evidence from the TEMPRANO, START and HPTN052 trials which showed improved M&M following initiation of ART, regardless of CD4 cell count, supporting recommendations for immediate treatment;
-Reducing risk of onward transmission at a time of higher VL
-Possible limitation of the viral reservoir to significantly below that seen when treatment is deferred
What should be done for co-infection with HBV and HIV-2?
Treat with ART that provides activity against both viruses.
The increased risk of mortality in people with both HBV/HIV-1 co-infection appears to be reduced, but NOT completely eliminated, by initiation of ART, WHY?
One possible explanation for this is a persistently higher prevalence of ongoing HBV viraemia in co-infected people on TDF compared to HBV mono-infection.
The underlying mechanism remains unclear, and signature drug resistance mutations have not been identified.
HBsAg loss following treatment initiation appears to be higher in HBV/HIV-1 and is more likely to occur in people with a low BL CD4 count, WHY?
One proposed explanation for this is rapid immune reconstitution when ART is initiated in these individuals.
Studies of co-infection have shown that HBsAg is lost in up to 22% of people with HIV-1 and HBV, depending on the duration of follow-up
Fill in the blank: The basic methodology for genotypic HIV-2 resistance testing involves extraction of viral RNA from plasma, reverse transcription to complementary (c)DNA, and _______.
[Nested PCR amplification of specific regions of this cDNA]
What is a significant finding regarding the decline in CD4 cell count in HIV-2 in the absence of detectable viraemia?
Decline can occur even without detectable viraemia.
What is the recommendation regarding the timing of ART initiation according to USA/WHO/EACS/UNAIDS?
Start as soon as diagnosis to prevent disease progression and transmission.
What is the challenge in managing virological failure in HIV-2?
Limited treatment options and higher likelihood of resistance development.
True or False: The evidence base correlating viral load with treatment benefit in HIV-2 is strong.
False.
What is an indicator condition in the context of HIV-2?
Clinical conditions associated with an undiagnosed HIV prevalence of >1/1000.
What is the implication of the finding that mortality off-treatment is substantial in HIV-2?
Supports universal treatment.
What is the effect of ART on the risk of new HIV-1 infection among individuals with HIV-2 mono-infection?
ART is likely to be protective against new HIV-1 infection.
What is the recommended initial treatment regimen for PLWH-2?
2 NRTI + one of: Second generation INSTI OR Ritonavir-boosted PI
What is NOT recommended for the treatment of HIV-2?
2DR currently used for treatment of HIV1, NNRTIs,
Fusion inhibitor ENFUvirtide,
ZDV/DDI/STV
HIV-2 is intrinsically resistant to NNRTI due to the differing structure of the NNRTI-binding pocket in HIV2.
Reduced phenotypic sensitivity to these PIs: Atazanavir, Fosamprenavir and Tipranavir
ZDV/DDI/STV are not recommended due to mitochondrial toxicity.
Which ARVs are approved to treat HIV-2?
There are NO approved drugs to treat HIV-2 and most in vitro drug sensitivity and resistance data are derived from group A HIV-2
Which NRTI are preferred as the backbone in treatment for HIV-2?
TDF/FTC
What are suggested alternative NRTI backbones if TDF is not suitable?
- TAF/FTC
- ABC/3TC (if clinical reason to avoid BOTH TDF/TAF)
Why is Tenofovir preferred over Abacavir?
Greater activity in the presence of viral resistance
Some evidence of success using TDF/FTC in 2nd-line ttt, including in a patient with the Q151M RT mutation
What are the recommended third agents for treatment-naive individuals?
- DTG
- Darunavir/r
No data DTG vs DRV/r—> DTG more tolerable and less DDI
What are the alternative 3rd agents?
Bictegravir
-RTG
-Elvitegravir/c
-Lopinavir/r should be reserved for those who can not tolerate all the above.
When is DTG recommended to be given as 1)50mg OD 2)50mg BD
1) For ttt-naive pts and no pre-existing INSTI resistance.
2)Pre-exisiting INSTI resistance and when given with EFV/RIF.
What is the dosing recommendation for DTG in HIV-2 pts? and why?
50mg BD
Given the potential for resistance development and limited treatment options.
**If an individual is consistently aviraemic prior to starting treatment, use of the 50mg OD can be considered.
What is the recommended dosing for Darunavir/r? and why?
DRV/r (600/100mg) BD
Same reason as for DTG dose
What should be considered when selecting treatment for HIV-1 and HIV-2 co-infection?
Viral load and resistance profiles for BOTH viruses
*if there is a clinical reason to start ttt before a definitive diagnosis is made, ART is started as for HIV-2 using BD dosing of either DTG/Darunavir/b.
What monitoring should be done if NOT on ART?
*CD4 counts at BL and then 3-6M (intervals depending on the BL value and rate of decline of CD4).
*VL at BL and then every 6M
*BL testing for NRTI, PI and INSTI resistance should b performed prior to starting ART; a sample shud b retained if testing not possible at that time.
When should CD4 count be measured after starting or changing ART?
CD4 count should b measured at 1, 3 and 6M
THEN
3-6M thereafter depending on nadir CD4 count.
When should the VL be measured after starting or changing ART?
-If the pre-ttt VL was detected:
VL should b measured at 1,3 and 6M then 3-6M thereafter
-If the pre-ttt VL Not detected:
VL should b measured at 1M then 6M
**VL should be repeated if became detectable after being maximally suppressed —> if repeatedly detected —> Testing for drug R should b done.
What is the recommendation for pregnant women with HIV-2 regarding ART?
Start ART if not already on it
If on established ART at conception —> continue
*Undetectable VL should NOT be used as factor to delay ttt, as VT may have occurred in this situation.
*May additionally prevent complications should the VL become detectable later in pregnancy.
What is the preferred ARV regimen for pregnant women with HIV-2?
TDF/FTC + DRV/r
DTG may be used/continued as a preferred 3rd agent, taking into consideration the possible risks and benefits for the woman.
Case discussion with experts with experience of managing HIV-2 is recommended for ALL pregnant women.
Women with HIV-2 who wish to conceive should be informed about the possible risks associated with DTG use around the time of conception.
What is the risk of VT of untreated HIV-2?
< in HIV-1 but is not zero.
Data from the pre-HAART era indicate a transmission risk of between 0.6%-4.0%
(unttt HIV-1 VT risk 10-20% –> with intervention <1%)
What should be done for infants at very low/low risk of vertical transmission (VT)?
Receive ZDV monotherapy for 2 weeks and 4 weeks
What should be done for infants at high risk of VT?
Receive triple therapy with ZDV/3TC/RTG
What defines treatment failure in HIV-2?
- Detection of HIV-2 plasma RNA in at least 2 consecutive tests
- Decline in CD4 cell count and/or
- Persistence/emergence of HIV/AIDS specific symptoms
What should be done in the case of virological rebound?
-Attempt Genotype resistance testing
-Algorithmic resistance mutation should b utilized if resistance is detected.
-Specialist advice from a clinician with experience
-Fully active agents should b used to construct a 2nd line regimen in the case of resistance, though it may be necessary to continue partially active agents in order to maximise overall regimen activity
How do you analyse mutations for HIV-2?
The HIV2EU group has published HIV-2 resistance mutations and an online mutation analysis algorithm is available.
In case of VR/F and no R found, what should be done?
-ID barriers to adherence
-Proactive ttt switching to more tolerable drugs may be important
What additional drugs may yield activity against HIV-2?
- Zidovudine
- Maraviroc
R5 tropic viruses have shown sensitivity to Maraviroc in vitro.
R5-tropism prediction algorithms are available, but v3 loop sequencing is NOT routinely available in the UK.
What is the recommendation for PEP and PrEP for sexual exposure to HIV-2?
Same as for HIV-1
What should be considered when using PEP after confirmed exposure to HIV-2?
Follow-up HIV testing should account for the longer window period for serological tests
