STIs

Question 1

What is the mode of transmission for HIV?

Answer 1

Exchange of bodily fluids (blood, semen, genital fluids, breast milk) via:

• unprotected sexual intercourse with an infected person
• Sharing infected syringes & needles *IV drug users
• Mother-to-child transmission during pregnancy, at birth or through breast-feeding
  -Transfusion of contaminated blood & blood products

Question 2

State the goals of antiretroviral therapy (ART) in HIV infection

Answer 2

1. Reduce HIV-associated morbidity & mortality
2. Prolong duration & quality of survival
3. Restore & preverse immunologic function
4. Maximally & durably suppress plasma HIV viral load
5. Prevent HIV transmission

Question 3

What are the surrogate markers used in managing patients on ART?

Answer 3

1. CD4 count
   *normal range: 500-1400/mm3
   MOST impt lab indicator of immune function in HIV-infected pts
   STRONGEST predictor of subsequent disease progression & survival
   - Used to assess response to ART (assessed at baseline, q3-6months after treatment initiation, q12months after adequate response
   *adequate CD4 response: INCREASE in CD4 count (50-150/mm3) during FIRST YEAR of therapy
   - Used to assess the need to initiate/ discontinue prophylaxis for opportunistic infections eg. pneumocystis pneumonia prophylaxis when CD4 < 200/mm3
2. plasma HIV RNA (viral load)
   MOST impt indicator of RESPONSE to ART; useful in predicting clinical progression
   - Measured before initiation of therapy, within 2-4 weeks (no later than 8 weeks) after treatment initiation/ modification, thereafter q4-8weeks UNTIL viral load suppressed
   *effective regimen: viral suppression (UNDETECTABLE HIV RNA level) by 8-24weeks
   **in pts on stable regimen & suppressed viral load: monitoring q3-6months

Question 4

Describe the benefits & limitations of earlier ART initiation

Answer 4

initiate ART ASAP (unless clinical and/or psychosocial factors) regardless of CD4 count -> reduces morbidity & mortality associated with HIV infection + prevents HIV transmission

BENEFITS
- Maintains HIGHER CD4 COUNT -> prevent potentially irreversible damage to immune system
- Decreased risk for HIV-associated complications (may sometimes occur even when CD4 count >350cells/mm3): tuberculosis, non-Hodgkin’s lymphoma, Kaposi’s sarcoma, peripheral neuropathy, HIV-associated cognitive impairment
- Decreased risk of non-opportunistic conditions: CVD, renal/ liver disease, non-AIDS associated malignancies & infections
- Decreased risk of HIV transmission to others

LIMITATIONS
- Treatment-related SE & toxicities
- Drug resistance development (incomplete viral suppression) -> loss of future treatment options
- Transmission of drug-resistant virus (patients who do not maintain FULL virologic suppession)
- Less time for patient education -> may affect adherence
- Increased total time on medication -> greater chance of treatment fatigue
- Increased costs

Question 5

What are the current 1st-line agents for antiretroviral therapy (list common agents, relevant benefits & risks)

Answer 5

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - Abacavir, Lamivudine, Tenofovir, Emtricitabine, Zidoovudine
- Established dual backbone of combination ART (with INSTIs)
- Renal elimination (little DDI) BUT renal dose adjustment for renal impairment needed (except Abacavir)
AE related to mitochondrial toxicity (lactic acidosis, hepatic steatosis // LIPOATROPHY): Z>T=A=L
**Abacavir: genotypic testing for HLA-B701 NEEDED before starting - only initiate if negative (if hypersensitivity occurs, discontinue DO NOT RECHALLENGE), avoid in high CVD risk patients
AE: mainly N/V/D (Tenofovir: can decrease bone mineral density/ cause renal impairment // Emtricitabine: hyperpigmentation // Zidoovudine: can cause bone marrow suppression)

integrase Strand Transfer Inhibitor (INSTI): Dolutegravir, Bictegravir, Raltegravir, Elvitegravir
- (bictegravir & dolutegravir) good virologic effectiveness
- High genetic barrier to resistance (B, D > R, E)
- Generally well tolerated
*ADR: weight gain, diarrhea, nausea, headache
// IF preexisting psychiatric conditions: depression, suicidality
** DDI: lowered bioavailability with concurrent POLYVALENT CATIONS
** Bica/Dolute: CYP3A4 substrates, increases SCr (inhibition of tubular secretion of creatinine; NO REAL RENAL IMPAIRMENT)
** Raltegravir: Pyrexia, increases creatinine kinase (rhabdomyolysis RISK)
- elvitegravir rarely used -

Question 6

What are the recommended ART combinations for newly started ART-naive patients?

Answer 6

2 NRTIs + 1 INSTI:
- Tenofovir + emtricitabine + Bictegravir (TEB)
- Tenofovir + emtricitabine + Dolutegravir (TED)
- Abacavir + lamivudine + dolutegravir (ALD)

1 NRTI + 1 INSTI:
- Emtricitabine + Dolutegravir (ED)
*NOT for individuals with: HIV RNA >500k copies/mL / Hep B coinfection (requires 2 antivirals for therapy) / if ART needs to be start before results of genotypic resistance/ HBV testing available

Question 7

List the major toxicities & DDI associated with various classes of ARTs

Answer 7

NRTIs: mitochondrial toxicity (lactic acidosis, hepatic steatosis // lipoatrophy), renal elimination -> renal dose adjustment in renally impaired patients (except abacavir)

INSTIs: weight gain, N/V/D, *preexisting psychiatric pts: depression, suicidality; DDI with polyvalent cations, CYP3A4 inhibitors/inducers (B/D/E)

NNRTIs: low genetic barrier to resistance *cross-resistance, skin rash, SJS (R<E), QTc prolongation; DDI: CYP450 (each are mixed inhibitor/inducer)

PIs: Metabolic complications (dyslipidemia, insulin resistance), Morphologic complications (Fat maldistribution: lipohypertrophy), GI (N/V/D), liver toxicity, increased risk of osteopenia/osteoporosis; DDI: CYP3A4 inhibitor/substrates

Fusion inhibitors: no appreciable drug interactions, injection site reactions, RARE hypersensitivity, increased bacterial pneumonia

CCR5 antagonists: abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper RT infections, hepatotoxicity, orthostatic hypotention; DDI: CYP3A4 inhibitor/inducers

Question 8

Who should be tested for HIV?

Answer 8

IV drug users
Persons who have unprotected sex with multiple partners
Man who have sex with Max (MSM)
Commercial Sex workers (CSW)
Persons treated for STDs (increased risk)
Recipients of multiple blood transfusions
Sexually assaulted individuals
Pregnant women *compulsory for all pregnant women

Question 9

Diagnosis of HIV infection

Answer 9

• Serum antibody detection via enzyme immunoassay antibody tests (HIV EIA) OR Western Blot
  -HIV RNA detection/ quantification (Viral load) via nucleic acid amplification (PCR)

Question 10

Clinical presentation of an individual with HIV

Answer 10

*different stages

Acute (primary) HIV infection: flu-like illness with swollen lymph nodes, fever malaise, rash (lasts 2-3 weeks)

Asymptomatic stage: NO signs or symptoms
*persists for many years

Persistent generalised Lymphadenopathy: persistent UNEXPLAINED enlarged lymph node in necks, underarms & groin for >3months

AIDS & related condition (end-stage): *CD4 count <200/mm3 -> risk of opportunistic infections (TB, recurrent bacterial pneumonia, Pneumocystis Carinii pneumonia, candidiasis, cytomegalovirus) including organs lungs/ eyes/ GIT/ nervous system/ skin
Systemic symptoms (fever, unexplained weight loss, diarrhea) are common
Rare cancers (lymphoma, Kaposi sarcoma) may be found

Question 11

What are the other available targets for antiretroviral therapy (apart from NRTIs & INSTI; list common agents, relevant benefits & risks)

Answer 11

Non-NRTIs (NNRTIs): Rilpivirine (DRUG OF CHOICE), Efavirenz
- Long half-lives
- Less metabolic toxicity (hyperlipidemia, insulin resistance) than some PIs
* LOW genetic barrier to resistance; cross resistance potential
*ADR: skin rash, SJS (R<E), QTc prolongation
(Rilpi: depression, headache VS Efa: neuropsychiatric SE, increase in LDL-C & triglycerides, hepatotoxicity, rash, hyperlipidemia
DDI: CYP450 (mixed inducers/inhibitors)
*Rilpi: use with PPIs CONTRAINDICATED (oral absorption decreased w increased gastric pH)

Protease inhibitors (PIs): Ritonavir, Lopinavir, Atazanavir, Darunavir, Fosamprenavir (coformulated with rito/ cobicistat)
- High genetic barrier to resistance
- PI resistance less common
*Metabolic complications (dyslipidemia, insulin resistance); Morphologic complications: Fat MALDISTRIBUTION (lipoHYPERtrophy)
**ADE: GI (N/V/D), liver toxicity *esp with chronic Hep B/C, INCREASED risk of osteopenia/ osteoporosis
**DDI: CYP3A4 inhibitors & substrates

Ritonavir: potent CYP3A4, 2D6 inhibitor; SE: paresthesia (numbness of extremities), taste perversion
Darunavir/ Atazanavir: Good GI tolerability, less lipid effects; (D: skin rash, concern for SJS *sulphonamide // A: absorption depends on low pH -> CI with use of PPIs, hyperbilirubinemia, prolong QT interval, skin rash)

*Ritonavir/ cobicistat as CYP3A4 INHIBITORS -> used as PK enhancers to INCREASE conc of PIs/ elvitegravir (INSTI)

Fusion (entry) inhibitors: Enfuvirtide
- No appreciable drug interactions
- Subcutaneous injection, 2x/day
*ADR: injection site reaction (erythema/induration, nodules/cysts, pruritis, ecchymosis), RARE hypersensitivity (fever, rash, chill, hypotension), increased bacterial pneumonia

CCR5 Antagonist: Maraviroc/ Selzentry:
*only for individuals carrying HIV strain where CCR5 receptor is used to enter CD4 cells -> co-receptor TROPISM ASSAY before initiation
**needs to be CCR5 PREDOMINANT (if dual/ mixed tropism/ other -> DONT USE)
*CYP3A4 substrate
ADR: abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper RT infection, hepatotoxicity, orthostatic hypotension

Question 12

Reasons for HIV therapy failure

Answer 12

Adherence (>95% adherence required for successful HIV therapy)
Resistance
Drug toxicities
Provider experience
DDI
Dosing schedules & requirements
Regimen potency

Question 13

What are the legally notifiable STIs?

Answer 13

• Gonorrhea, non-gonococcal urethritis/ syphilis/ chlamydia/ genital herpes
• HIV/ AIDs
• Viral hepatitis (A/B)

*notification to be made within 72h of diagnosis
* reporting for surveillance/ document effectiveness of national guidelines EXCEPT HIV/AIDS: for case reporting/ contact tracing (partner notification necessary)

Question 14

What is the mode of transmission for STIs?

Answer 14

Sexual contact with infected persons

Direct contact of BROKEN SKIN with open sores, blood or genital discharge

Recipient of CONTAMINATED BLOOD

Mother-to-child during pregnancy (syphilis, HIV), at childbirth (chlamydia, gonorrhea, HIV) or breastfeeding (HIV)

Question 15

Risk factors for STIs

Answer 15

unprotected sexual intercourse
number of sexual partners/ sexual partner with multiple sexual partners
MSM
prostitution (CSW)
illicit drug use

Question 16

Prevention of STIs

Answer 16

*ABCs
Abstain, Be faithful (monogamous r/s with uninfected partner), Condom use
Avoid drug use & sharing needles
pre-exposure vaccination *HPV, Hep B
pre- & post- exposure prophylaxis (HIV)

Question 17

Goals of management & prevention of STIs

Answer 17

• reduce related morbidity, progression to complicated disease
• Prevent HIV infection (increased risk of HIV transmission/ acquisition in patients with genital herpes/ gonococcal/ syphilis infections)
• Prevent serious complications in WOMEN (STIs are main preventable cause of infertility, prevent HPV -> prevent cervical cancer)
• Protect babies

Question 18

Management of Gonorrhea infection

Answer 18

pathogen involved: Neisseria gonorrhoeae
Transmission: sexual contact, mother-to-child during childbirth
Diagnosis: gram-stain of genital discharge, NAAT (nucleic acid amplification test)
Sites of infection: Urethra, Cervix, Rectum, Pharynx, Conjunctiva **can be disseminated (multiple sites)
Presentation: *CAN BE ASYMPTOMATIC
M - purulent urethral discharge, dysuria, urinary frequency
F - mucopurulent vaginal discharge, dysuria, urinary frequency

*abx for UNCOMPLICATED gonococcal infections
**treat for gonorrhea -> treat for CHLAMYDIA as well (similar clinical presentation, treat UNLESS chlamydia infection excluded)
- Ceftriaxone 500mg IM (single dose, pts <150kg) *if >/=150kg: 1g
OR
- Gentamicin 240mg IM (single dose) + Azithromycin 2g PO (single dose)
OR
- Cefixime 800mg PO (single dose) *not avail in SG

PLUS

Doxycycline 100mg BD PO x7d

**FQs not recommended (increasing resistance)
**test of cure is RECOMMENDED

Management of sex partners: partners within last 60 days to be tested & evaluated; if >60d most recent one to be treated
ABSTAIN 7d AFTER treatment, until after all sex partners are treated

Question 19

Possible complications of gonorrhea infection?

Answer 19

M: Prostatitis, Epididymitis, urethral stricture, DISSEMINATED DISEASE
F: Pelvic inflammatory disease, ectopic pregnancy, infertility, DISSEMINATED DISEASE

*disseminated disease: skin lesions, tenosynovitis (inflammation of fluid-filled synovium within tendon sheath), monoarticular arthritis

**complications of chlamydial infections similar

Question 20

Management of Chlamydial infections

Answer 20

Pathogen: Chlamydia trachomatis
Presentation: SIMILAR to gonorrhea, perhaps milder (purulent urethral discharge (M)/ mucopurulent vaginal discharge (F), dysuria, urinary frequency) **may be asymptomatic
Diagnosis: NAAT (nucleic acid amplification test)
Infection sites: as per gonorrhea (urethra, cervix, rectum, pharynx, conjunctiva *multiple site infection possible)

Antibiotics:
Doxycycline 100mg BD PO x 7d ***
OR
Azithromycin 1g PO (single dose)
OR
levofloxacin 500mg PO OD x7d

*erythromycin not recommended (GI S/E reduces adherence)
**test-of-cure not required (treatment highly effective) UNLESS specific concerns (pregnancy non-adherence) OR symptoms persist

Sex partner management: within 60d: all to be evaluated & tested, if >60d most recent one to be treated
*ABSTAIN 7d after treatment for SINGLE DOSE regimen; ABSTAIN until treatment over for 7d regimen + resolution of symptoms (if present)

***doxycycline counseling points:
take with food (reduce GI upset)
take with glass of water & sit upright for at least 30mins (prevent heartburn)
Do not take with Ca/ Fe/ milk (Take 2h apart)
SE: GI, photosensitivity

Question 21

Syphilis diagnosis (Tests)

Answer 21

Diagnosis: darkfield microscopy of exudates from lesions
*requires 2 serological test - treponemal & non-treponemal

Treponemal: use of treponemal antigen to detect treponemal antibody (more sensitive & specific -> used as CONFIRMATORY tests)
*may maintain reactive for life -> NOT for monitoring

Non-treponemal: use of non-treponemal antigen (cardiolipin) to detect treponemal antibody
1. Veneral Disease Research Laboratory (VDRL) slide test
2. Rapid Plasma Regin (RPR) card test
* +ve result -> ANY stage of syphilis
quantitative -> reflects most dilute serum conc with +ve reaction (eg. 1:16 +ve -> 1:32 NO reaction)
**CORRELATES WITH DISEASE ACTIVITY -> for monitoring
**not interchangeable; if used one test for monitoring need to STICK TO IT
*non-treponemal test titres usually declines after treatment; can become NON-reactive over time

Question 22

Syphilis management

Answer 22

Pathogen: treponema pallidum (gram -ve)
Transmission: sexual contact, mother-to-child during pregnancy (transplacental)
Clinical presentation: MULTIPLE STAGES; primary (local symptoms) -> secondary (multisystem eg. patchy alopecia) -> latent *asymptomatic -> tertiary (complications) -> neurosyphilis (CNS infection)
Diagnosis: darkfield microscopy of exudates from lesions
2 serological tests (VDRL, RPR)

Antibiotics
Primary, Secondary, early latent (<1y):
IM Benzathine Pen G 2.4 MU (single dose)
OR
PO Doxycycline 100mg BD x 14d

Late latent (>1y/ unknown duration), Tertiary:
IM Benzathine Pen G 2.4 MU once a week x 3doses
OR
PO Doxycyline 100mg BD x 28d

Neurosyphilis:
IV Crystalline Pen G 3-4 MU q4h
OR 18-24 MU per day AS continuous infusion
x 10-14d
OR
IM Procaine (released over 24h) Pen G 2.4 MU daily
PLUS
PO Probenecid 500mg QDS
x10-14d
*penicillin allergy:
IV/IM ceftriaxone 2g daily x 10-14d
(if concern for cross-sensitivity, skin test to confirm penicillin allergy, desensitise if necessary)

Monitoring:
- Jarisch-Herxheimer reaction: acute febrile reaction accompanied by headache/ myalgia/ other symptoms that usually occur within 1st 24h after ANY therapy for syphilis (antipyretics will help BUT NOT PREVENT)
- Primary/Secondary/Latent syphilis: Quantitative VDRL/ PRP at 3/6/12/18/24 months
*treatment success: decrease of VDRL/RPR titre by at least FOUR-fold (eg. 1:64 to 1:16)

**treatment failure at 6months:
- shows signs & symptoms of disease
OR
- Failure to decrease VDRL or RPR titre by FOUR-fold OR INCREASES (1:16 to 1:64)
-> retreat & reevaluate for unrecognised neurosyphilis

Sex partner management: all at risk should be evaluated & treated (if +ve)
ABSTAIN from sexual contact with new partners UNTIL LESIONS COMPLETELY HEALED
*need CAREFUL ASSESSMENT OF WHETHER THEY HAVE RESPONDED & IF SYMPTOMS RESOLVED by doctor

Question 23

Overview of Genital Herpes management

Answer 23

Pathogen: Herpes Simplex Virus (HSV-1 & HSV-2) *most recurrent genital herpes by HSV-2
HSV cycle: primary mucocutaneous infection -> infection of NERVE GANGLIA -> establishment of latency -> reactivation -> recurrent outbreaks/ flares
Transmission: transfer of bodily fluids, intimate skin-to-skin contact
*vesicles develop over 7-10days, take 2-4weeks to heal (intermittent viral shedding from epithelial cells - may not be symptomatic during shedding & transmission)

**CHRONIC, LIFE-LONG INFECTION

Presentation: painful multiple vesicular/ ulcerative lesions // Local itching, pain, tender inguinal lymphadenopathy // Flu-like symptoms (fever/ malaise/ headache) during first few days after lesion appears // PRODROMAL symptoms (mild burning, itching/ stinging) prior to appearance of recurrent lesions
*symptoms less severe in recurrent disease (less lesions/ heal faster/ milder symptoms)

Virologic tests: viral cell culture/ NAAT (HSV DNA from genital lesions)
Type-specific serologic test
*antibodies to HSV develop during 1st several weeks after infection, persist indefinitely -> NOT useful for 1st episode infection (takes 6-8weeks for serological detection)

GOALS of therapy: relieve symptoms, shorten clinical course, prevent complications & recurrence, reduce transmission

NON-PHARM:
warm saline bath, symptom management (analgesics/ anti-itch), good genital hygiene

ORAL acyclovir & valacyclovir
- helps reduce viral shedding by 7d
- helps shorten duration of symptoms by 2d
- helps shorten time to heal 1st episode by 4d
*DOES NOT prevent latency/ affect frequency & severity of recurrent disease
**MAX benefit when initiated @ earliest stage of disease (within 72h)

Topical antivirals have minimal clinical benefit + can cause local irritation -> use discouraged

Counseling: natural history of disease/ inform current & future partners/ possibility of transmission in asymptomatic pts/ abstinence during lesions or prodromal symptoms/ need for consistent use of latex condoms/ risk of HSV transmission can be reduced by daily use of (val)acyclovir

Sex partner management:
SYMPTOMATIC -> evaluate & treat in same manner as infected pts w genital lesion
ASYMPTOMATIC: enquire history of genital lesions, encourage self-examination for lesions, seek medical attention early if lesions shows (may be offered serologic type testing for HSV-2)

Question 24

Pharmacological management of 1st episode of genital herpes

Answer 24

Acyclovir:
PO 400mg TDS x 7-10d
IV 5-10mg/kg q8h x2-7d, complete with PO for total 10d (for severe disease/ complications that require hospitalisation

Valacyclovir:
PO 1g BD x 7-10d

Acyclovir inhibits viral DNA polymerase; F ~10-20%, half-life 3h (valcyclovir L-valine ester of acyclovir; rapidly & COMPLETELY converted to acyclovir & valine; F~55%, half-life 3h)

Counseling points:
take before/after food (after if GI upset)
Hydrate to prevent crystallisation in renal tubules
ADR: malaise, headache (main for valacyclovir), N/V/D

**treatment can be EXTENDED if healing incomplete after 10d therapy

Question 25

Pharmacological management of RECURRENT genital herpes

Answer 25

*almost all persons with SYMPTOMATIC 1st episode of genital herpes infection will experience RECURRENT flares (median: 4 recurrences the year after 1st symtomatic episode)

1. Chronic Suppressive therapy:
   PO acyclovir 400mg BD
   OR
   PO valacyclovir 1g OD
   OR
   PO valacyclovir 500mg PO OD (may be less effective for pts w frequent recurrences)
   *discuss on annual basis whether or not to continue - frequency of HSV-2 recurrence decreases over time UNLESS complicated disease course (immunosuppressed) -> stay on chronic suppressive therapy
   - helps reduce frequency of recurrence by 70-80%
   - NO symptomatic outbreaks
   - improved QoL
   - long-term safety & efficacy
   - reduced risk of transmission (in combi w consistent condom use + abstinence during recurrence)
2. Episodic therapy: take when recurrence occurs
   PO acyclovir 800mg BD x5d
   OR
   PO acyclovir 800mg TDS x 2d
   OR
   PO valacyclovir 500mg BD x 3d
   OR
   PO valacyclovir 1g OD x5d
   - shorten duration & severity of symptoms
   - less costly (vs chronic suppression)
   - pts more likely to be compliant
   *requires initiation of therapy to be within 1d of lesion onset/ during prodrome that precedes some outbreaks
   * does not lessen risk of transmission

*famiclovir also possible but not available in sg