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  • This picture shows the global distribution of HIV as of the end of 2002. An estimated 42 million persons are infected with HIV worldwide. Unfortunately, like most other scourges and infectious diseases, the burden of the disease is the highest in countries and regions most ill equipped and least resourceful to combat it. The most resource poor countries of sub-Saharan Africa and South and SE Asia are the worst hit areas.
  • In 2002 alone, the number of new HIV infections was a staggering 5 million. Again, the preponderance of these infections was in sub-saharan Africa followed by south and SE Asia.
  • If you look at the death numbers, the geographic distribution is similar to the incidence and prevalence of HIV and AIDS. In 2002 over 3 million persons died from AIDS displacing TB as the number one killer infectious disease in the world. This ranking of TB vs. AIDS has been debated by many, since a large number of patients with AIDS, especially those in Africa and Asia, go on to develop TB, and it is unclear to me how many of TB deaths were classified as AIDS. Regardless of how you classify it, the underlying message is very clear – there are far too many people dying with this disease.
  • These numbers translate to about 14,000 new infections per day. Which means that by the time I finish this presentation, about 600 persons would have acquired infection, or by the time I finish reading this slide, about 10 new infections would have occurred. 95% of these occur in the developing countries and a large number in children under the age 15.
  • AIDS has extorted a huge toll in terms of lives lost, since the beginning of the epidemic. In the first 20 years over 20 million persons have succumbed to this infection, most of them in the developing world, impacting those countries in manners unimaginable – both in terms of human tragedy which can never be adequately quantified and economically.
  • Slide courtesy of C. J. Cohen, MD.
  • CID 2001;33:1417 Fischl 8 th CROI 2001; Abst. 528
  • * Regimen adherence measurement at week 24 or last assessment while on randomized therapy
  • Gender, race and age were balanced across treatments PSS = Number of drugs in OB regimen to which virus was phenotypically sensitive
  • Sources: Davey et al. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, Calif./Justice et al. In: Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, Calif.

10331 10331 Presentation Transcript

  • Principles of HIV Therapy Simple is Better! Adeel A. Butt, MD Assistant Professor of Medicine and Infectious Diseases University of Pittsburgh Director, VAPHS HIV-ID Clinics Center for Health Equity Research and Promotion Member of Academic Research Council A non-profit organization dedicated to improving medical education and fostering research
    • Objectives
    • To tell you why we should care
    • To tell you why the care is not optimal
    • To share with you how some of us feel how this may be improved
    • To describe when to initiate treatment and some initial regimens
    Principles of HIV Therapy
  •  
  • Estimated number of adults and children newly infected with HIV during 2002 Total: 5 million Western Europe 30 000 North Africa & Middle East 83 000 Sub-Saharan Africa 3.5 million Eastern Europe & Central Asia 250 000 East Asia & Pacific 270 000 South & South-East Asia 700 000 Australia & New Zealand 500 North America 45 000 Caribbean 60 000 Latin America 150 000
  • Estimated adult and child deaths from HIV/AIDS during 2002 Total: 3.1 million Western Europe 8 000 North Africa & Middle East 37 000 Sub-Saharan Africa 2.4 million Eastern Europe & Central Asia 25 000 East Asia & Pacific 45 000 South & South-East Asia 440 000 Australia & New Zealand <100 North America 15 000 Caribbean 42 000 Latin America 60 000
  • About 14 000 new HIV infections a day in 2002
    • - More than 95% are in developing countries
    • - 2000 are in children under 15 years of age
    • - About 12 000 are in persons aged 15 to 49 years, of whom:
      • almost 50% are women
      • about 50% are 15–24 year olds
  • Estimated adult and child deaths due to HIV/AIDS from the beginning of the epidemic to end 1999 Western Europe 210 000 North Africa & Middle East 70 000 Sub-Saharan Africa 13.7 million Eastern Europe & Central Asia 17 000 East Asia & Pacific 40 000 South & South-East Asia 1.1 million Australia & New Zealand 8 000 North America 450 000 Caribbean 160 000 Latin America 520 000 Total: 16.3 million Over 20 million dead by now
  • Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000 Source: United Nations Population Division, 1996 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Average life expectancy at birth, in years 65 60 55 50 45 40 35 Zimbabwe Zambia Uganda Botswana Malawi
  • Goals of Antiretroviral Therapy Control of viral replication Prevention or delay of progressive immunodeficiency Delayed progression to AIDS Prolonged Survival Decreased selection of resistant virus
  • Treatment Impact: CD4 Cell Count and Plasma HIV-1 RNA Level 150 100 50 0 -50 -100 -150 -200 CD4 + Cell Count Plasma HIV-1 RNA 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 Monotherapy Double RTI Combinations Highly Active Antiretroviral Therapy Years +
  • Who Should be Treated
    • HIV ELISA positive, confirmed with Western blot
    • HIV RNA >55,000 copies/ml
    • CD4 <350 cells/mm 3
    • Special considerations:
      • Pregnant women
      • Acute HIV infection
      • Exposed healthcare workers
  • Highly Active Antiretroviral Therapy
    • Four approved classes of drugs in the HAART regimens
      • Nucleoside and nucleotide reverse transcriptase inhibitors
      • Non-nucleoside reverse transcriptase inhibitors
      • Protease inhibitors
      • Fusion inhibitors
  • Currently Available Drugs
    • Nucleoside analogue reverse transcriptase inhibitors
      • Zidovudine (AZT, Retrovir)
      • Lamivudine (3TC, Epivir)
      • Stavudine (D4T, Zerit)
      • Didanosine (DDI, Videx)
      • Zalcitabine (DDC)
      • Abacavir (Ziagen)
    • Nucleotide …
      • Tenofovir (Viread)
  • Currently Available Drugs
    • Non-nucleoside reverse transcriptase inhibitors
      • Nevirapine (viramune)
      • Delavridine (rescriptor)
      • Efavirenz (sustiva)
    • Fusion Inhibitors
      • Enfuvirtide (T-20)
  • Currently Available Drugs
    • Protease Inhibitors
        • Indinavir (crixivan)
        • Nelfinavir (viracept)
        • Ritonavir (norvir)
        • Saquinavir soft gel (fortovase)
        • Amprenavir (agenerase)
        • Lopinavir/ritonavir (kaletra)
        • Amprenavir/ritonavir
  • What is the Best Initial Treatment
    • What we know
      • Two is better than one
      • Three is better than two
    • What we are trying to find out
      • Is four better than three????
    • IS THERE A GOLD STANDARD?
  • ABC of HIV Therapy
    • Here is what I am NOT going to talk about
    • All previous HIV Studies
    • Details and comparisons of all regimens
  • Choice of Initial Regimen 2 PI (ritonavir as booster) 2 NRTI 1 nucloeotide RTI (tenofovir) 2 NRTI 3 rd NRTI is abacavir 3 NRTI 1 NNRTI 2 NRTI 1 PI 2 NRTI
  • Choice of Initial Regimen
    • NRTIs
      • AZT – 2 tab
      • Epivir – 2 tab
      • Zerit – 2 tab
      • Videx (DDI) – 1 tab (new EC formulation)
      • Hivid (DDC) – I don’t ever use it
      • Abacavir – 2 tab
      • Tenofovir – 1 tab
    • Combivir (AZT + Epivir) – 2 tab
    • Trizivir (AZT + Epivir + Abacavir) – 2 tab
  • Choice of Regimen
    • NNRTIs
        • Nevirapine (Viramune) (2 tab)
        • Efavirenz (Sustiva) (3 cap)
        • Delavradine (Rescriptor) (6 or 12)
    • PIs
        • Indinavir (6 or 12 cap)
        • Nelfinavir (10 tab)
        • Ritonavir (don’t even go there)
        • Saquinavir soft gel (18 cap)
        • Amprenavir (16 cap)
        • Lopinavir/ritonavir (6 cap)
  • Complexity of Regimens
  • Final Regimen
    • Trizivir – 2 tab
    • Combivir + ABC – 4 tab
    • Combivir + NEV – 4 tab
    • Combivir + EFV – 5 tab/cap
    • D4t + EPI + EFV – 7 tab/cap
  • Why Does Treatment Fail?
    • Intolerance
    • Infection with a resistant virus
    • Malabsorption
    • NON-ADHERENCE TOPS THE LIST
      • Rates of adherence have a direct correlation with success of HAART 1
      • Near perfect viral suppression in DOT trials 2
  • Reasons for Non-Adherence
    • Psychiatric issues
    • Drug use
    • Social circumstances
    • Privacy issues
    • Adverse events
    • COMPLEXITY
      • Number of pills, number of doses, food restrictions, drug interactions
  • What Non-Adherence Can Do Paterson Ann Int Med 2000;133:21-30
  • Are Simple Regimens As Effective?
    • COMBINE Study
      • ZDV+Epivir+NEV vs. ZDV+Epivir+Nelfinavir
    • CNA3014
      • Combivir+abacavir vs. Combivir+indinavir
    • CNAF3007
      • Combivir+abacavir vs. combivir+nelfinavir
  • Adherence at Week 24* in CNA3014 Percentage of Subjects 56% 25% 74% 45%
  • Enfuvirtide (ENF, T-20) in Combination with an Optimized Background (OB) Regimen vs. OB Alone in Patients with Prior Experience or America and Brazil (TORO 1) Resistance to Each of the Three Classes of Approved Antiretrovirals (ARVs) in North
  • TORO 1: Demographics and Baseline Characteristics ENF+OB OB Total (N=326) (N=165) (N=491) Baseline RNA 5.2 5.2 5.2 (median, log 10 ) Baseline CD4+ cell count 76 87 80 (median, cells/mm 3 ) Prior ARVs (median) 12 12 12 Years ARV use (median) 7.0 7.1 7.0 Prior ADEs (N, %) 273 (84%) 148 (90%) 421 (86%) PSS at entry (mean) 1.7 1.8 1.7
  • TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24 -1.70 -0.76 -2 -1 0 (Delta=0.93 P<0.0001) Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF) OB alone ENF (T-20) + OB N=165 N=326 Change from BL (log 10 copies/ml)
  • TORO 1: CD4+ Cell Count Change from Baseline at Week 24 76 32 0 50 100 Change from BL (Cells/mm 3 ) P=0.0001 Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF) OB alone ENF (T-20) + OB
  • Averting Failure — Promote Adherence
    • HAART has increased long-term survival of patients with HIV
      • Before HAART, median survival: 8 to 10 years
      • After HAART, median survival: may be 36 years
    • Drug “holidays” or treatment interruptions result in rapid viral rebound within 2 to 3 weeks of treatment discontinuation
    • Simplification of dosing regimens to twice or once daily may improve long-term adherence
  • Averting Failure
    • Initiate therapy at the optimal time
        • Patient factors, viral load, CD4
    • Simplify regimens
    • Provide support
        • Social, medical, psychiatric, rehabilitation
  • Other Factors Associated with Poor Adherence
    • active depression,
    • risk factor for HIV other than male-male sex,
    • nonwhite race,
    • low income,
    • lower level of education,
    • psychiatric disorders
    • active alcoholism
  • Summary
    • Chose patients to treat carefully
    • With appropriate treatment, HIV is quite controllable, like any other chronic disease
    • Missing a couple of doses a week may mean losing the game
    • Less is better, when it comes to the number of pills
  • Summary
    • When to start treatment
        • CD4<350
        • VL> 55,000
    • Choice of initial regimen
        • 3 drugs
    • Appropriate prophylaxis
        • Primary: PCP, MAC
        • Secondary: PCP, MAC, Toxo, candidiasis, CMV, etc.