ORGB 423 Lecture Notes - Lecture 10: Luc Montagnier, Hiv Vaccine, Entry Inhibitor
12 Jun 2018
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Department
Course
Professor
MIMM466 – Viral Pathogenesis
2018-01-22 LEC 9, 10 HIV Global Epidemiology & Treatment Advances
History of HIV
• 1930: Retrovirus passed from chimpanzee à human
• 1981: First case of “immunodeficiency” disease reported in gay men in the US
• 1982: same immunodeficiency disease diagnosed in Europe, CDC names disease “AIDS”
• 1983: Heterosexual spread of AIDS, new retrovirus isolated in pre-AIDS patient by Luc Montagnier
o Hemophiliacs recognized at great risk of AIDS
• 1984: Retrovirus isolated by Montagnier in France, shown to be the cause of AIDS by Robert Gallo
o CD4 identified as HIV receptor, European reports describe 2 “different” AIDS epidemics in
homosexuals and people emigrating from Africa
o 7,700 AIDS cases reported in the US and 762 in Europe
• 1985: Blood test for HIV, sequence of HIV, first international AIDS conference
• 1986: LAV and HTLV-III renamed HIV
• 1987: AZT introduced as treatment, HIV infected persons barred from entering US
• 1990: 8-10M HIV-infected persons worldwide
• 1991: Red ribbon becomes international AIDS symbol, ddC approved as HIV inhibitor, first combination
therapy of ddC + AZT
• 1992: India funds AIDS control project with >15% of health budget
• 1993: AZT-resistant virus, HIV replication in lymph nodes, 3TC approved for clinical use
o 14-15M infected worldwide
• 1994: AZT reduces mother-child transmission of HIV
• 1995: first protease inhibitor approved
• 1996: Home testing for HIV, CCR5 identified as a co-receptor, deletion in CCR5 gene confers protection
o First non-nucleoside RT inhibitor
o Now: 3 kinds of inhibitors; nucleoside RT inhibitors, protease, and non-nucleoside RT inhibitors
• 1997: No cure because cannot eradicate reservoirs, death toll begins to drop due to use of HAART
o Clinton sets goal of 10 years for AIDS vaccine
• 1998: First clinical trial for AIDS vaccine (eventually failed), side effects of HAART start to appear
o Post-exposure prophylaxis program (makes people who already have HIV less likely to transmit)
o Multi-resistant HIV documented
• 1999: Origins of HIV traced to chimpanzee virus, nevirapine shown to reduce mother-child transmission
o Needle sharing causes increase of HIV in Russia
• 2000: International AIDS conference in South Africa, Botswana estimates ¼ of adults are HIV+
o 34.3M people HIV+
• 2001: HIV budding described, AIDS labeled “most devastating epidemic”
o UN secretary calls for establishment of fund to fight AIDS, Tuberculosis, Malaria
o South African court orders government to make nevirapine available to pregnant women and
establish MCT program
• 2002: Powerful anti-HIV host factor APOBEC3G discovered
• 2003: First HIV fusion inhibitor, enfuviritide, approved, 40% of population infected in Swaziland (highest
infection rate), VaxGen phase III clinical trial for AIDS vaccine fails
o 14,000 people infected with AIDS every day
• 2004: FDA approves oral AIDS test, Botswana provides treatment to 50% of those in need
• 2005: HIV infection increasing in the US in African Americans, growing momentum for antiviral therapy for
AIDS prevention, AZT goes off patent, 4 generic forms of AZT pop up in the US
• 2006: Male circumcision diminishes man-woman AIDS transmission by 50%, GALT targeting explored
o First one-a-day pill (Atripla) approved for sale, CDC calls for routine testing for HIV
o Nearly 40M HIV infected persons, over 25M dead of AIDS
• 2006-2017: improvement of treatments, introduction of integrase inhibitors, increased interest in finding cure
o UNAIDS sets “90, 90, 90 goal” to diagnose 90% of HIV, suppress viral load in 90% of infected, and
put 90% of infected on treatment
Major progress: HIV has become a chronic, manageable condition
Summary of anti-retroviral drugs
• Right now there are 6 major classes, that target:
o Virus entry, reverse transcription, integrase, transcription, virus assembly, and protease
processing
• Untreated progression: HIV RNA rises sharply, then decreases because infection is temporarily controlled
o During this time, there is a steady decline of CD4 T cells
o When CD4 T cell count reaches a critical density (~200 cells per mm3), HIV RNA increases again,
leading to death
• Progress with anti-retroviral treatment: Can control HIV RNA, and keep it at a very low level while your
body restores the CD4 T cells in the blood
Recommended Antiviral (ARV) regimen
• ARV regimen for a treatment-naïve patient generally consists of:
o 2 nucleoside RT inhibitors (NRTIs) along with a third active ARV drug from 1 of 3 classes:
§ Integrase strand transfer inhibitor (INSTI)
§ Non-nucleoside RT inhibitor (NNRTI)
§ Protease inhibitor (with a pharmacokinetic enhancer) (PI)
• Recommended initial regimens for most people with HIV
o Dolutegravir/abacavir/lamivudine: (2 nucleoside inhibitors + dolutegravir) patients who are
HLAB*5701(-)
o Dolutegravir + tenofovir/emtricitabine
o Evitegravir/cobicistat/tenofovir/emtricitabine
o Raltegravir + tenofovir/emtricitabine
• HIV RNA <100,000 copies/mL and/or HLA-B*5701 (-): Boosted PI + 2 NRTIs
• HIV RNA <100,000 copies/mL, CD4 > 200 cells/mm3: NNRTI + 2 NRTIs
• HLA-B*5701(-), HIV RNA < 100,000 copies/mL: INSTI + 2 NRTIs
• Given the many excellent options for initial therapy, selection of a regimen for a particular patient should be
guided by factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction
potential, resistance testing results, comorbid conditions, access, and cost
Characteristics to consider in All Persons with HIV
• Pretreatment HIV RNA level (viral load) and CD4 count
o If RNA level is too high or CD4 count is too low, certain treatments will not work
• HIV genotypic drug resistance testing results should guide regimen decision
o Based on current rates of transmitted drug resistance to different ARV medications
o Focus on testing for mutations in the RT and protease genes, also test for INSTI resistance mutations
• HLA--B*5701 status
• Individual preferences
• Anticipated adherence to the regimen
Specific comorbidities or other conditions
• Cardiovascular disease, hyperlipidemia, renal disease, liver disease, osteopenia/osteoporosis or conditions
associated with BMD loss, psychiatric illness, neurologic disease, drug abuse or dependency requiring
narcotic replacement therapy
• Pregnancy or pregnancy potential
• Coinfections: HBV, hepatitis C virus (HCV), TB
Regimen-specific considerations
• Regimen’s genetic barrier to resistance (low genetic barrier = HIV can easily evolve)
• Potential adverse effects
• Known or potential drug interactions with other medications
• Convenience (e.g., pill burden, dosing frequency, food requirements…etc.)
• Cost
Document Summary
2018-01-22 lec 9, 10 hiv global epidemiology & treatment advances. Major progress: hiv has become a chronic, manageable condition. Recommended antiviral (arv) regimen: arv regimen for a treatment-na ve patient generally consists of, 2 nucleoside rt inhibitors (nrtis) along with a third active arv drug from 1 of 3 classes: Protease inhibitor (with a pharmacokinetic enhancer) (pi: recommended initial regimens for most people with hiv, dolutegravir/abacavir/lamivudine: (2 nucleoside inhibitors + dolutegravir) patients who are. Characteristics to consider in all persons with hiv: pretreatment hiv rna level (viral load) and cd4 count. Individual preferences: anticipated adherence to the regimen. Regimen-specific considerations: regimen"s genetic barrier to resistance (low genetic barrier = hiv can easily evolve, potential adverse effects, known or potential drug interactions with other medications, convenience (e. g. , pill burden, dosing frequency, food requirements etc. , cost. Problems: viral transmission, drug resistance, transmission of resistance, drug toxicity, long-term consequences of.
