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疫学

マクロな疫学

AIDS発症はHICではPcPが最頻，LMICでは結核が最頻

ウイルス学

細胞感染

1. CD4 receptorに接合attach
2. CCR5/CXCR4に結合　←chemokine receptor antagonist
3. 細胞膜融合
4. viral RNAの逆転写（細胞質）　←RTase inhibitor;NRTI, NNRTI
5. proviral RNA integration（核内）　←integrase inhibitor
6. ウイルスタンパクのポリペプチドへの分解と再構成（細胞質）　←protease inhibitor

HIV-1 typing

• Group M
  • clade: A,B,C,...,K,CRFs
    • CRF=circulating recombinant forms
• Group N
• Group O
• Group P

予防

1. Frequent testing
2. Treatment as prevention; U=U
3. PrPE
4. PEP within 72 hrs
5. Condom

PrEP

• 1 pill "Truvada"
  • Tenefovir + Emtricitabine
  • inhibits reverse transcriptase
• 20 USD/month
• >86% reduction
• high concentration in genital issues

• Administration options

1. daily - for anal and vaginal sex
2. event-based - for anal sex
3. ≧4 doses/week - anal sex

daily PrEP

• 1 tablet/day
• effective for anal sex 1 day after of commencement
• effective for vaginal sex 7 days after of commencement

event-based PrEP

• 2 tabltes at 2-24 hours before anal sex + 1 tablet 24-48 hours after the sex
• not effective against vaginal sex

how to stop

• have to continue for a certain duration after the last sex

monitoring

• test renal function every 3 mo
  • annually for eGFR>90 or <40y/o
• check bone history including FRAX score
• test HIV, hepB, Urea, Electrolytes
• U/A
• offer STIs screening

contraindication of PrEP

• Renal dysfunction; eGFR<60
• Osteoprorosis
• event-based dosing is option for contraindicated people

clincal trials of PrEP

• PROUD study
  • 86% reduction of HIV
• IMPACT study

Prevention of Mother to Child transmission (PMTCT)

• Primary prevention in women of childbearing age
• Voluntary counseling and testing (VCT) provided in prenatal care
• ART for PMTCT

WHO Consolidated Guidelines in 2021

• Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 16 July 2021
  • refer to 'Chapter 3.4 Infant prophylaxis' on pp.91 (134th as PDF)
• Mother
  • Urgently commence ART for all HIV-infected pregnant and post-partum women irrespective of time or viral load
• All Infants
  • Daily AZT+NVP from 0d to 6w
• Breastfed infants of high risk
  • Additional AZT+NVP or NVP alone from 6w to 12w
• Breastfed infants of mother under ART
  • Additional daily NVP from 6w to 12w
• Replacement fed infants of mother under ART
  • Additional daily NVP from 6w to 10-12w

WHO Clinical staging

Stage	1	2	3	4
Skin		Herpes zoster Papular pruritic eruptions Seborrheic dermatitis Fungal nail infections		Herpes simplex infection (oral, genital) > 1 month Talaromycosis (Asia only)
Oral GI tract		Angular cheilitis Oral ulcer, recurrent	Oral Candidiasis Oral hairy leukoplakia (EBV-associated) Acute necrotizing ulcerative stomatitis/gingivitis/periodontitis Diarrhea > 1 month, unexplained	Esophageal Candidiasis Cryptosporidiasis, chronic Isosporiasis, chronic
Respiratory		URIs, recurrent	Bacterial LRIs Pulmonary TB, pluribacillary	Severe bacterial LRIs, recurrent Pulmonary TB, paucibacillary Pneumocystis pneumonia (PcP)
Neurological				CNS toxoplamosis (Toxoplasmoma) HIV encephalopathy CNS cryptococcal infection (Cryptococcoma) Progressive multifocal leukoencephalopathy
Systemic	Asymptomatic Acute HIV infection Lymphadenopathy, persistent	Weight loss <10%, unexplained	Weight loss >10%, unexplained Fever > 1 month, unexplained Sever bacterial infections (LRI, bone/joint infections, meningitis) Anemia < 8g/dL of Hb, unexplained Thrombocytopenia < 50[math]\displaystyle{ \times }[/math]10[math]\displaystyle{ ^9 }[/math]/L, unexplained	HIV wasting syndrome Extrapulmonary TB Cytomegalovirus infection Non-typhoidal salmonellosis (NTS), recurrent Coccidioidomycosis (America only) Histoplasmosis Atypical disseminated leishmaniasis HIV-associated nephrophathy HIV-associated cardiomyopathy
Malignancy				Kaposi's sarcoma Lymphoma Cervical carcinoma HIV-associated solid tumors

Stage	Skin	Oral & GI tract	Respiratory	Systemic	Malignancy
1				Asymptomatic Acute HIV infection Lymphadenopathy, persistent
2	Herpes zoster Papular pruritic eruptions Seborrheic dermatitis Fungal nail infections	Angular cheilitis Oral ulcer, recurrent	URIs, recurrent	Weight loss <10%, unexplained
3		Diarrhea > 1 month, unexplained Oral Candidiasis Oral hairy leukoplakia (EBV-associated) Acute necrotizing ulcerative stomatitis/gingivitis/periodontitis	Pulmonary TB, pluribacillary Bacterial LRIs	Weight loss >10%, unexplained Fever > 1 month, unexplained Sever bacterial infections (LRI, bone/joint infections, meningitis) Anemia < 8g/dL of Hb, unexplained Thrombocytopenia < 50[math]\displaystyle{ \times }[/math]10[math]\displaystyle{ ^9 }[/math]/L, unexplained
4	Herpes simplex infection (oral, genital) > 1 month Talaromycosis (Asia only)	Esophageal Candidiasis Cryptosporidiasis, chronic Isosporiasis, chronic	Pulmonary TB, paucibacillary Pneumocystis pneumonia (PcP) Severe bacterial LRIs, recurrent	HIV wasting syndrome TB, extrapulmonary Cytomegalovirus infection CNS toxoplamosis (Toxoplasmoma) HIV encephalopathy CNS cryptococcal infection (Cryptococcoma) Progressive multifocal leukoencephalopathy Non-typhoidal salmonellosis (NTS), recurrent coccidioidomycosis (America only) histoplasmosis Atypical disseminated leishmaniasis HIV-associated nephrophathy HIV-associated cardiomyopathy	Kaposi's sarcoma Lymphoma Cervical carcinoma HIV-associated solid tumors

Treatment

WHO｜Update of recommendations on first- and second-line antiretroviral regimens - Policy brief

The Lighthouse - A Centre for Comprehensive HIV/AIDS Treatment and Care in Malawi

HIV drug interaction checker

原則

• 異なる2クラスで異なる3剤によるcombination Txが必須
• 生涯治療

Combination

• NRTI - Nucleoside reverse transcriptase inhibitor
• NNRTI - Non-Nucleoside reverse transcriptase inhibitor
• PI - Protease inhibitor
• INI - Integrase inhibitor

NRTI + NRTI + {NNRTI or INI or PI}

scheme

NRTI Nucleoside Reverse Transcriptase Inhibitor
Tenofovir TDF	Once daily well tolerated	effective for Hep B	Renal toxicity (tubular damage) Fanconi syndrome hypophosphataemia glucosuria proteinuria Osteoporosis
Tenofovir alafenamide fumarate TAF	prodrug of tenofovir less side effects than TAF
Lamivudine 3TC	backbone for all regimens well tolerated 3TC and FTC have almost the same molecular structures	effective for Hep B
Emtricitabine FTC
Zidovudine AZT	Twice daily well tolerated the world-first anti-HIV		macrocytic anemia lipodystrophy
Abacavir ABC	in case of failure/intolerance of other NRTIs		febrile hypersensitivity with HLA-B5701 Caucasians need HLA-testing before treament

NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor
Efavirenz EFV	1st choice in NNTRIs	neuropsychiatric side effects dizzyness, insomnia, nightmares, depression, psychoses rash gynecomastia 5-6% in Africa
Nevirapine NVP	not effective against HIV-2	rash to Stevens Johnson syndrome hepatic toxicity interact with rifampicin never use in HIV-TB

INI Integrase Inhibitor
Dolutegravir DTG	well tolerated	insomnia dizzyness paresthesia weight gain
Raltegravir RAL

PI Protease Inhibitor
Lopinavir-Ritonavir LPV-r	Twice daily	diarrhea metaboilc disturbance dyslipidemia impaired glucose tolerance lipodystrophy CYP3A4 interactions
Atazanavir ATV-r	Once daily	hyperbilirubinemia, jaundice interact with rifampicin

WHO Guideline 2019

• WHO reference page is here

Adults and adolescents

1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Alternative 1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV 400mg	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Special circumstances

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Children

1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Alternative 1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Special circumstances

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Neonates

1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Alternative 1st line

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

Special circumstances

NRTI
Tenofovir TDF
Tenofovir alafenamide fumarate TAF
Lamivudine 3TC
Zidovudine AZT
Abacavir ABC
NNRTI	INI	PI
Efavirenz EFV	Dolutegravir DTG	Lopinavir-Ritonavir LPV-r
Nevirapine NVP	Raltegravir RAL	Atazanavir ATV-r

NRTIs

• Nucleoside analogue 競合的にNRTを阻害する

• Tenofovir TDF 最重要
  • Once daily
  • hep Bにも有効
  • 腎毒性；尿細管障害
    • 尿dip stickでモニター
  • 骨塩減少
    • 小児には使いにくい
  • Tenofovir alafenamide fumarate TAF；新しいプロドラッグ
• Zidovudine AZT
  • 最初のARV in 1987
  • 骨髄抑制；大球性貧血
  • Twice daily
• Lamivudine 3TC /Emtricitabine FTC
  • Lamivudine 3TC
    • すべてのレジメンでbackbone
    • high tolerance
    • hep Bにも有効
    • 耐性閾値が低い
  • Emtricitabnine FTC
    • 3TCのlong-acting type
• Abacavir ABC
  • 他薬intolerance時の代替
    • 主として小児
  • HLA-B5701陽性者でのfebrile hypersensitivity
    • HLA-B5701陽性者はアフリカでは極めて稀

NNRTIs

• Efavirenz EFV
• Nevirapine NVP

• Efavirenz EFV
  • NNRTIの1st choice
  • little interaction with Tb drugs
  • dizzyness, insomnia, nightmare, depression, psychoses
  • rash
  • gynecomastia; 6% in Africa

• Nevirapine NVP
  • あまり使われなくなった
  • Rash→Stevens-Johnson
  • 肝毒性
    • 女性に多い
    • CD4>250でリスク12倍
  • HIV-2に無効
  • RifampicinがNVP濃度を下げる

INIs

• Dolutegravir DTG
• Raltegravir RAL

• very well tolerated
• rapid viral suppression
• lesser drug interaction
• high threshold resistance

• Doltegravir DTG
  • 1st line としてEFVに取って代わった
  • once daily
  • no food interaction
  • neural tube defectがわずかに増加する；妊娠可能女性では十分な説明と同意

PIs

• 2nd line
• 下痢
• dyslipidemia, 耐糖能異常
• lipodystrophy syndrome
• CYP3A4阻害
• boosting PIs；PIをごく少量の他のPI ritonavirと併用
  • -rを付す
  • Lopinavir-Ritonavir LPV-r
  • Atazanavir ATV-r
    • 高ビリルビン血症，黄疸

WHO 1st line

1. TDF+3TC+DTG
2. TDF+3TC+EFV

WHO 2nd line

1. NRTI+NRTI+INI
2. NRTI+NRTI+PI

CPT

Co-trimoxazole preventive therapy

• 480-960mg/日 ST合剤

Treatment of advanced HIV

Minimum package of diagnostics for advanced HIV

IRIS

Immune reconstitution inflammatory syndrome

• importance to monitor IRIS
• CD4 count が低い状態で日和見感染を開始するときはARTは最低限1ヶ月空けてから
  • paradoxical IRIS

フォローアップ

• 治療効果判定にはviral load
• CD4 countは初診時には有用だがフォローアップには無用；viral loadが大事