1
Q
HIV: mode of transmission
A
via specific body fluids
Blood, semen, genital fluids, breast milk
2
Q
HIV: Risk factors
(who to conduct testing for)
A
IV drug users
Person who have unprotected sex with multiple partners
Man who have sex with man
Commercial sex workers
Persons treated for STDs ⇒ increased risk of HIV
Recipients of multiple blood transfusion
Persons who have been sexually assaulted
Pregnant women
3
Q
HIV: clinical presentation
(1) acute (primary) infection
A
Occurs soon after contracting HIV
Flu-like illness: swollen lymph nodes, fever, malaise & rash ⇒ lasts 2-3 weeks
4
Q
HIV: clinical presentation
(2) asymptomatic
A
No signs & symptoms
Persists for many years
5
Q
HIV: clinical presentation
(3) persistent generalised lymphadenopathy
A
Persistent unexplained lymph node enlargement in neck, underarms & groin
More than 3 months of symptoms
6
Q
HIV: clinical presentation
(4) AIDS & related conditions
diagnostic criteria & symptoms (organs involved & systemic s)
A
Requirements for AIDS diagnosis:
* AIDS = CD4 <200 cells /mm3 or presence of AIDS-defining diseases
Healthy individuals: CD4 500-1200 cells /mm3
* Immune system too weak to fight against invading virus & bacteria
* Person succumb to Opportunistic infections
Organs involved: lung, eyes, GIT, nervous system & skin
Systemic symptoms: fevers, unexplained weight loss, diarrhoea
Rare cancers
7
Q
Goals of anti-retroviral therapy
A
- Reduce HIV-associated morbidity & mortality
- Prolong duration & quality of survival
- Restore & preserve immunologic function
To avoid reaching state of being immunocompromised; maintain CD4 T cell count - Maximally & durably suppress plasma HIV viral load to undetectable levels
- Prevent HIV transmission
8
Q
Surrogate markers of HIV
A
- CD4 Cell count
- Viral load
9
Q
Surrogate markers of HIV: CD4 count
what it indicates
A
Normal individuals: 500-1200 cells/ mm3
Indicator of immune function
strongest predictor of subsequent disease progression + survival
10
Q
Surrogate markers of HIV: CD4 count
purpose
A
To determine urgency for initiating antiretroviral therapy
* Note: current → to start treatment when patient is infected with virus to prevent CD4 cell count from decreasing
* Late start to treatment = unlikely recovery of CD4 cell count to normal levels
To assess response to antiretroviral therapy (compare with initial diagnosis)
(1) assessed at baseline, (2) every 3 to 6 months after treatment initiation & (3) every 12 months after adequate response
To assess need for initiating/ discontinuing prophylaxis for opportunistic infections
11
Q
Surrogate markers of HIV: CD4 count
effective treatment definition
A
increase in CD4 count in the range of 50 to 150 cells/mm3 during the first year of therapy
12
Q
Surrogate markers of HIV: Viral load
indication
A
Amount of virus in plasma
Most important indicator of response to antiretroviral therapy
Help with predicting clinical progression
13
Q
Surrogate markers of HIV: Viral load
Assessment timeline
A
- Before initiation of therapy
- Within 2-4 weeks after treatment initiation OR modification (no later than 8 weeks)
- Every 4-8 weeks until viral load suppressed
- Those on stable regime & suppressed viral load ⇒ every 3-6 months
14
Q
Surrogate markers of HIV: Viral load
effects of treatment
A
achieve viral suppression by 8-24 weeks
* No longer have detectable HIV RNA levels
15
Q
earlier ART initiation
indication & requirements
A
For all HIV-patients regardless of CD4 cell count
adherence: Require at least 95%, if not have risk of resistance
16
Q
earlier ART initiation: benefits
A
- Maintenance of higher CD4 count & prevention of potentially irreversible damage to immune system
- Decreased risk for HIV-associated complications
- Decrease risk of non-opportunistic conditions
CVD, renal disease, liver disease & non-AIDS-associated malignancies and infection - Decreased risk of HIV transmission ⇒ positive public health implications
17
Q
earlier ART initiation: limitations
A
- Development of treatment-related SE & toxicities
- Development of drug resistance
Due to incomplete viral suppression; especially non-adherence
Loss of future treatment options - Transmission of drug-resistant virus for those without full virologic suppression
Important to check for resistance pattern of virus before initiating treatment - Lesser time for patient to understand HIV and its treatment + preparation for need of adherence
- Increased total time on medications → greater treatment fatigue
- Increased costs
18
Q
Recommended combinations (patients naive to ART)
A
2 NRTIs + 1 INSTI [First line]
1 NRTIs + 1 INSTI
19
Q
Recommended combinations: 1 NRTI & 1 INSTI requirements
A
- HIV RNA >500k copies/ mL (extremely high)
- HBV coinfection
HBV → requires 2 AV against HepB virus (tenofovir, emtricitabine, lamivudine) - Starting on ART before results of HIV genotypic resistance testing/ HBV testing
Must confirm that patient does not have co-infection of HBV & resistance against drug before treatment
20
Q
ART drug classes
A
- NRTI
- INSTI
- NNRTI
- PI
- fusion inhibitor
- CCR5 antagonist
21
Q
(1) NRTI: drugs
A
lamvudine
abacavir
zidovudine
emtricitabine
tenofovir
22
Q
(1) NRTI: Advantages
A
Established in combination ART
Renal elimination → fewer DDI
23
Q
(1) NRTI: disadvantages
A
AE related to mitochondrial toxicity → rare but serious
* Lactic acidosis & hepatic steatosis (fatty infiltration)
* Morphologic complication ⇒ Lipoatrophy (lost of fat)
* Zidovudine>Tenofovir=Abacavir=Lamivudine
Requires dose adjustment in renally impaired patients (except abacavir)
24
Q
(1) NRTI: Adverse effects
lamvudine, tenofovir, emtricitabine
A
lamvudine
Minimal toxicity; N/V/D
tenofovir
Minimal toxicity; hyperpigmentation, N/D
emtricitabine
* N/V/D
* Possible renal impairment
* Decrease in bone mineral density ⇒ increased risk of osteoporosis & osteopenia
25
(1) NRTI: Adverse effects
| zidovudine, abacavir
**Abacavir**
* N/V/D
* Hypersensitivity reaction in patients with HLA-B*5701
*Discontinue if occurs & do not rechallenge
Require testing for HLA-B5701 before initiation*
* Association with MI ⇒ avoid in high CVD risk patients
**zidovudine**
* N/V/D
* Myopathy
* Bone marrow suppression ⇒ causes anemia/ neutropenia
(To monitor FBC)
26
(2) INSTI: drugs
bictegravir
raltegravir
elvitegravir
dolutegravir
27
(2) INSTI: Advantages
| B&D
Bictegravir & dolutegravir ⇒ good virologic effectiveness
High genetic barrier to resistance [B&D > R&E]
Generally well tolerated
28
(2) INSTI: Disadvantages
| bioavailability, DDI
Bioavailability lowered by concurrent administration of polyvalent cations
Bictegravir, dolutegravir & elvitegravir ⇒ CYP 3A4 substrates
29
(2) INSTI: Adverse effects
| common ones
weight gain, diarrhoea, nausea & headache
Depression & suicidality in those with pre-existing psychiatric conditions
30
(2) INSTI: Adverse effects
| bictegravir & elvitegravir
increase SCr
Inhibits tubular secretion of creatinine
31
(2) INSTI: Adverse effects
| raltegravir
Pyrexia
Elevation of CK ⇒ rhabdomyolysis
32
(3) NNRTI: drugs
efavirenz
Rilpivirine
33
(3) NNRTI: Advantages
* Long t1/2 ⇒ OD dosing
* Less metabolic toxicities than with some PIs
Hyperlipidemia, insulin resistance
34
(3) NNRTI: Disadvantages
| GB, CR, DDI, S, Q
* Low genetic barrier for resistance
* Cross resistance among approved NNRTIs
* Skin rash, SJS [R < E]
* Potential for CYP450 drug interactions → inducers & inhibitors
**Efavirenz**: CYP3A4 substrate, CYP2B6 and 2C19 inducer
**Rilpivirine**: CYP3A4 substrate, oral absorption is reduced with increased gastric pH; use with PPIs is contraindicated.
* QTc prolongation
35
(3) NNRTI: AE
| Efavirenz, Rilpivirine
**Efavirenz**
* Rash
* Hyperlipidemia: increased LDL-C & TG
* Neuropsychiatric SE: dizziness, depression, insomnia, abnormal dreams, hallucination
* Hepatotoxicity
**Rilpirivine**
CNS: Depression & headache
36
(4) protease inhibitor: drugs
Liponavir
Azatanavir
Darunavir
Fosamprenavir
Ritonavir
37
(4) protease inhibitor: Advantages
High genetic barrier to resistance
38
(4) protease inhibitor: Disadvantages
* Metabolic complications → dyslipidemia, insulin resistance
* GI SE → N/V/D
* Liver toxicity (especially with chronic hepatitis B or C)
* CYP3A4 inhibitors & substrates: potential for DDI
* Morphologic Complications → Fat maldistribution (Lipohypertrophy)
* Increased risk of osteopenia/osteoporosis
39
(4) protease inhibitor: characteristics
| ritonavir
* Potent CYP3A4, 2D6 inhibitor
* PK enhancer → combined with other PI [Lopinavir/ritonavir] to increase the other PI concentration levels
**SE**: paresthesia (numbness of extremities) & taste perversion
40
(4) protease inhibitor: characteristics
| azatanavir
(+) Good GI tolerability & less lipid effects
* Absorption depends on low pH
Contraindication with PPIs
**SE**: hyperbilirubinemia, prolong QT interval, skin rash
41
(4) protease inhibitor: characteristics
| darunavir
(+) Good GI tolerability & less lipid effects
(-) Skin rash & concern for SJS
Due to **sulfonamide** component
42
(5) fusion inhibitor: drug & characteristics
| administration & DDI
Enfuvirtide
SC injection BD
no DDI
43
(5) fusion inhibitor: AE
* **Injection site reaction**→ erythema/ induration, nodules/ cyst, pruritis, ecchymosis
* **Rare hypersensitivity** → fever, chills, decrease BP, rash
* Increased bacterial pneumonia
44
(6) CCR5 antagonist: drug
maraviroc
45
(6) CCR5 antagonist: requirement
Only for those with strains of HIV **using CCR5 receptor to enter CD4 cells**
* Need co-receptor tropism assay before initiation (to check which receptor HIV uses to enter cells)
* Must be **CCR5 predominant**
46
(6) CCR5 antagonist: potential DDI & AE
**Potential DDI**: CYP3A4 substrate
**ADR**:
Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension
47
STI caused by bacteria
Syphilis: Treponema pallidum
Gonorrhoea: Neisseria gonorrhoeae
Non-gonococcal urethritis
Chlamydia
48
STI caused by virus
herpes simplex virus (HSV)
HIV
49
Mode of transmission for STIs
* Mainly by sexual contact with infected person
* **Direct contact** of broken skin with open sores, blood or genital discharge
Must be deep/ big
* Receiving contaminated blood
Important to start on post-exposure prophylaxis
Usually screened to ensure no STI in blood
* From infected mother to child
During **pregnancy** → ie: syphilis, HIV
During **childbirth** → ie: chlamydia, gonorrhoea, HSV
**Breastfeeding** → ie: HIV
50
RF for STIs
* Unprotected sexual intercourse
* Number of sexual partner
Those with **multiple sexual partners**→ more likely to acquire & transmit STI
Those with **sexual contact with people who have multiple sexual partners**
* MSM
* Prostitution (CSW) → covers first 2 points
* Illicit drug use → ie sharing of needle by IV drug users
51
individual prevention methods of STI
* Abstinence & reduction of number of sexual partners
long-term, mutually monogamous relationship with an uninfected partner
* Barrier contraceptive methods
male latex condoms when used consistently & correctly
* Avoid drug abuse & sharing needles
* Pre-exposure vaccination
HPV (Human papillomavirus), Hepatitis B
* Pre- and Post-exposure prophylaxis → HIV
**Pre**: if viral load is not suppressed, partner is at risk of infection → to take AV pills continuously
**Post**: after possible exposure to virus
52
(B) Gonorrhoea: causative organism
Neisseria gonorrhoeae
53
(B) Gonorrhoea [&chlamydia] : transmission
sexual contact, mother-to-child during childbirth
54
(B) Gonorrhoea: diagnostic method
gram-stain of genital discharge, culture, NAAT
55
(B) Gonorrhoea [&chlamdymia] : possible infection to other sites
Urethritis → urethra; Cervicitis → cervix; Proctitis → rectal area; Pharyngitis → throat; Conjunctivitis
Disseminated → throughout the body
56
(B) Gonorrhoea [&chlamdymia] : clinical presentation (uncomplicated)
| male & female
**both**
Dysuria
Urinary frequency
**Male**
Purulent urethral discharge
**female**
Mucopurulent vaginal discharge
57
(B) Gonorrhoea [&chlamdymia] : clinical presentation (complicated)
| male & female
**both**
disseminated disease
**male**
Epididymitis
Prostatitis
urethral stricture
**female**
Pelvic inflammatory disease
Ectopic pregnancy, infertility
58
(B) Gonorrhoea: pharmacological management
| first line & alternative
**First line**
Ceftriaxone:
* 500 mg IM single dose for those <150kg
* 1g IM single dose for those ≥150kg
**Alternative (if ceftriaxone unavailable)**
* Gentamicin 240 mg IM in single dose AND
* Azithromycin 2g PO in single dose
PO doxycycline 100 mg BD x7 days **if chlamydia infection not excluded**
59
(B) Chlamdymia: causative organism
Chlamydia trachomatis
60
(B) Chlamdymia: diagnostic test
NAAT
61
(B) Chlamdymia: pharmacological management
| first line & alternative
**First line**
PO Doxycycline 100 mg BD x7 days
**Alternative (if ceftriaxone unavailable)**
PO Azithromycin 1g in single dose
OR
PO levofloxacin 500 mg OD x7 days
**Possible to use azithromycin as first line if adherence is of concern**
62
(B) Chlamdymia: requirements for testing of cure
pregnancy, non-adherence or **symptoms persist**
* Need to check for possibility of reinfection
63
(B) gonorrhea & Chlamdymia: management of sex partners
* Sex partners in last 60 days should be evaluated & treated
If last sexual exposure >60 days, to treat most recent partner
* Abstain from sexual activity for 7 days after treatment to minimise disease transmission
* Abstain from sexual intercourse until all sex partners are treated to minimise risk of reinfection
64
(B) syphilis: causative organism
Treponema pallidum
65
(B) syphilis: transmission
sexual contact, mother-to-child (transplacental during pregnancy)
66
(B) syphilis: diagnosis
Darkfield microscopy of exudates from lesions
2 serological tests ⇒ more common
67
(B) syphilis: diagnosis
serological tests
1. trepenomal test
2. non-trepenomal test
68
(B) syphilis: trepenomal test
| how it works, what it tells, limitation
* Use treponemal Ag to detect treponemal Ab (produced during infection)
* More sensitive & specific than non-treponemal test ⇒ used as confirmatory test
* May remain active for life → not for monitoring response to treatment
Ab remains present in body; not necessarily indicate current infection
69
(B) syphilis: non-trepenomal test
| what it tells, how it works
* To determine if infection is CURRENT or PAST
* Use nontreponemal Ag (cardiolipin) to detect treponemal Ab
* Positive tests → presence of any stage of syphilis
* Result reported in quantitative VDRL/ RPR test = **most dilute serum concentration with positive reaction**
Result of 1:16 positive ⇒ 1:32 no reaction seen (no Ab at that dilution)
* **Higher VDRL/ RPR = greater bacteria presence** (more Ab produced)
Ab titre correlate with disease activity ⇒ used to monitor response to treatment
* Non-treponemal test titres usually declines after treatment; becomes non-reactive with time
70
(B) syphilis: pharmacological management
primary/ secondary/ early latent (<1 year)
| regimen & penicillin allergy (+ counselling)
IM Benzathine penicillin G 2.4 million units x1 dose
**penicillin allergy**
PO doxycycline 100 mg BD x14 days
**Counselling**
* Take with food to reduce GI upset
* Take with glass of water & maintain upright at least 30 mins to prevent heartburn
* Do not take with milk, Ca or Fe ⇒ take 2 hours apart
**SE**
GI, photosensitivity
71
(B) syphilis: pharmacological management
tertiary/ unknown duration/ late latent (>1 year)
| regimen & penicillin allergy
IM Benzathine penicillin G 2.4 million units once a week x3 dose
**penicillin allergy**
PO doxycycline 100 mg BD x28 days
72
(B) syphilis: pharmacological management
neurosyphilis
| regimen & penicillin allergy
IV crystalline (benzyl) penicillin G 3-4 million units q4h or 18-24 million units q24h x10-14 days
OR
IM procaine penicillin G 2.4 million units OD + PO probenecid 500 mg QID x10-14 days
**penicillin allergy**
IV/ IM ceftriaxone 2 g OD x10-14 days
**Concerns for cross-sensitivity**
* Skin prick test to confirm penicillin allergy
* To desensitise if necessary
(1) Daily low level of exposure of allergen (penicillin) → build up to therapeutic dose
(2) Continue at therapeutic dose → if miss dose, should restart low dose again
73
(B) syphilis: formulation
PenG
| IM benzathine, IM procaine, IV crystalline
**IM benzathine** ⇒ released over a week (slower)
High sensitivity of syphilis from penG ⇒ low concentration of drug required
**IM procaine** ⇒ releases over a day + **IV crystalline** ⇒ high dose
Bacteria entering CSF → require high dose of penicillin G to reach CSF concentration
74
(B) syphilis: formulation
probenecid
| purpose
reduces secretion of penicillin ⇒ increases concentration of penicillin in systemic circulation
* Cannot give IM procaine alone in neurosyphilis; unable to achieve high enough CSF concentration
75
(B) syphilis: response upon treatment
Jarisch-Herxheimer reaction = **acute febrile reaction, frequently accompanied by headache, myalgia**, and other symptoms that usually occur **within the first 24 hours after any therapy **for syphilis
* **Antipyretics** will help but not prevent
76
(B) syphilis: monitoring of response
| syphilis & neurosyphilis, duration of tests
Primary / secondary/ Latent syphilis: Quantitative VDRL/ RPR at 3, **6, 12,** 18 & **24** months (using blood)
* treatment success = decrease of VDRL or RPR titre by at least fourfold (ie: 1:64 to 1:16)
Neurosyphilis: CSF examination (Quantitative VDRL/ RPR) every 6 month until CSF normal
77
(B) syphilis: indication of treatment failure
* show sign & symptoms of disease
* Failure to decrease VDRL/ RPR titre by fourfold OR VDRL/ RPR titre increase
ie 1:16 to 1:64
* Retreat & re-evaluate for unrecognised neurosyphilis
78
(B) syphilis: management of partners
* All at risk sexual partners should be evaluated for STIs & treat if test positive
* Persons receiving syphilis treatment must abstain from sexual contact with new partners **until the syphilis lesions are completely healed**
79
(V) Genital herpes: causative agent
HSV2 mainly
80
(V) Genital herpes: transmission
transfer of body fluids and intimate skin-to-skin contact
81
(V) Genital herpes: infection timeline
| development & healing of vesicles, viral shedding
Vesicles develop over 7-10 days; heal in 2-4 weeks
* Reactivation of virus → will have shorter healing time
Intermittent viral shedding from epithelial cells
* Possible even when person is asymptomatic
* Transmission can occur even without presence of vesicles
82
(V) Genital herpes: diagnosis methods
1. patient hx
2. virologic testing
3. type-specific serologic test
83
(V) Genital herpes: diagnosis
patient hx
Previous lesions
Sexual contact with similar lesions at genitals
84
(V) Genital herpes: virologic test
NAAT (PCR) for HSV DNA from genital lesions
85
(V) Genital herpes: type specific serologic test
| what is tested, problem for first-episode serology
Testing for Ab
* Ab to HSV develop during the first several weeks after infection & persist indefinitely
* Serology is not useful for first episode infection → takes between 6 & 8 weeks for serological detection following a first episode
Requires time for buildup of Ab to sufficient concentration for detection
Presence of HSV-2 antibody ⇒ anogenital infection
86
(V) Genital herpes: clinical presentation
| first infection
* classical painful multiple vesicular or ulcerative lesions (When vesicles break)
* local itching, pain, tender inguinal lymphadenopathy (lymph at inguinal)
* Flu-like symptoms (ie: fever, headache, malaise) during first few days after the appearance of lesions
87
(V) Genital herpes: clinical presentation
| recurrent
* Prodromal symptoms → mild burning, itching or tingling
* Symptoms less severe → less lesions, heal faster, milder symptoms
Due to previous immunity; presence of Ab reduces severity
88
(V) Genital herpes: supportive care & counselling
* Warm saline bath → relief discomfort
* Analgesia & anti-itch → symptomatic relief
* Good genital hygiene → prevent superinfection of bacteria
* Counselling about natural history
Inform that infection is lifelong + possible transmission even without vesicles; triggers for vesicles + reactivation is possible
89
(V) Genital herpes: drug choice
| MOA, clinical effects, when to start
acyclovir & valacyclovir
**Mechanism of action:** inhibit viral DNA polymerase → inhibit DNA synthesis & replication
**Clinical effects:**
* Reduce viral shedding by 7 days
* Reduce duration of symptoms by 2 days
* Reduce time to healing of 1st episode by 4 days
**Starting**
Maximum benefit ⇒ initiate at earliest stage of disease (within 72 hours)
90
(V) Genital herpes: first episode
acyclovir
| dose, F, t1/2, counselling points, SE
* PO 400 mg TDS x7-10 days
* IV 5-10 mg/kg q8h x2-7 days + PO for 10 days
For severe disease/ complications requiring hospitalisation/ herpes encephalitis
Usually for immunocompromised (will have higher viral load)
**F** = 10-20%; **t1/2** ~3 hours
**Counselling**
* Take with/ without food
After food if have GI upset
* Maintain adequate hydration ⇒ prevent crystallisation in renal tubules
**SE (general, non-specific)**
Malaise, headache, N/V/D
91
(V) Genital herpes: first episode
valacyclovir
| dose, F, t1/2, counselling points, SE
PO 1g BD x7-10 days
L-valine ester of acyclovir (prodrug)
Rapidly & almost completely converted to acyclovir & valine
**F** = 55%; **t1/2** ~3 hours
* Can give higher dose & less frequently
**Counselling**: similar to acyclovir including hydration
**SE**: mainly headache
92
(V) Genital herpes: recurrent
| definition
Median = 4 recurrences the year after first symptomatic episode
93
(V) Genital herpes: recurrent therapies
1. chronic suppressive therapy
2. episodic therapy
94
(V) Genital herpes: [1] chronic suppressive therapy
| drug & dosing
PO Acyclovir 400 mg BD
PO valacyclovir 1 g OD
95
(V) Genital herpes: [1] chronic suppressive therapy
| indications
* patients who have many recurrences
* Patients with complicated disease course (ie disseminated disease)
* immunocompromised hosts → may have severe disease state during reactivation of HSV
96
(V) Genital herpes: [1] chronic suppressive therapy
| advantages
* reduces the frequency of recurrences by 70%–80% in patients who have frequent recurrences (ie: >6 recurrences per year)
* Most will have no symptomatic outbreaks ⇒ improved QOL
* decreased risk of transmission
in combination with consistent condom use & abstinence during recurrences
Reduction in chance of viral shedding + barrier method
97
(V) Genital herpes: [1] chronic suppressive therapy
| disadvantages
Cost → daily dosing
Compliance → continuous dosing
98
(V) Genital herpes: [2] episodic therapy
| when to start
when patient have prodromal symptoms OR vesicles present
99
(V) Genital herpes: [2] episodic therapy
| drug & dose
Either one of the following:
* PO Acyclovir 800 mg
BD x5 days OR TDS x2 days
* PO valacyclovir 500 mg BD x3 days
* PO valacyclovir 1 g OD x5 days
100
(V) Genital herpes: [2] episodic therapy
| advantage
* **Shorten duration & severity** of symptoms
* **Less costly** compared to chronic suppression
* Patient more likely to be **compliant**
101
(V) Genital herpes: [2] episodic therapy
| disadvantage
* Requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks
* Does not reduce risk of transmission
Once patient is off AV → can shed virus & transmit HSV
102
(V) Genital herpes: management of sexual partners
* **Symptomatic** sex partners: evaluated & treated in the same manner as patients who have genital lesions.
* **Asymptomatic** sex partners of patients who have genital herpes should be **questioned concerning histories of genital lesions**, encouraged **to examine themselves for lesions and seek medical attention early if lesions occur**.
