update on hiv therapy elly t katabira, frcp department of medicine makerere university medical...
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Update on HIV Therapy
Elly T Katabira, FRCP
Department of Medicine
Makerere University Medical School
Scaling up Treatment Programs: Issues, Challenges & Best Practices
Dakar, Senegal, December 2, 2008
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The early days of HIV care
• Diagnosis of HIV infection was clinical
• Emphasis on care was on:Management of opportunistic infections and
cancersEarly diagnosisPrompt and effective treatment
Psychosocial supportPalliative careMinimise stigma
Health education on prevention
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The early HIV related Guidelines
• First international guidelines by WHO and CDCTargeting resource limitted settingsAIDS case surveillance definitionOctober 1985, Bangui, CARPublic Health experts + CDC representationRevised 1994
HIV serology optional – when available
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The early HIV related Guidelines
• Other guidelines followed including:WHO clinical staging systemManagement of opportunistic infectionsHIV prevention
On PMTCTAt the work place
Home care and counselingART
IAS-USAWHO
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“Slim Disease”/Wasting
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Kaposi’s sarcoma
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Kaposi’s sarcoma before and after chemotherapy
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Early days of antiretroviral therapy
• AZT and monotherapyPremature termination of the studies
Toxicity and short-lived response
• Dual therapy of NRTIsd4T, ddI, ddC Better than monotherapy but not good enough
Considered suitable for sub-Saharan Africa
• Triple therapy and the PIs – 1996The basis of the current ART strategies
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Development of International Guidelines
• Generated by a panel of experts in the relevant fieldsRegional representation
• Often evidence or consensus based or both Published researchClinical or field experience
• Subject to regular reviewWhen new evidence become available
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Major contentions of ART guidelines
• When to start ARTEarly vs delayed startWhat criteria to use
Clinical + CD4 count or viral load or bothWHO or CDC staging – for adults and children
• What to use as first line therapyTriple nukes and which onesUse of PIs as first line
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HIV-1 lifecycle
RT
Provirus
ProteinsRNA
DNA
RNA
DNA
DNA
RT
Viral protease
Reversetranscriptase
RNA
RNA
DNA
DNA
DNA
Entry
Integrase
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Continued Evolution of HAART 25 drugs and counting
1996 2006 1997 1998 1999 2000 2001 2002 2003 2004 2005
First protease
inhibitor (PI)approved
1995
First fixed-dose (triple) combination
approved
First fusion inhibitor approved
Number of new approved ARV agents(1996–2007)
5 0 2 2 1 1 2 1First fixed-dose (dual)
combination approved
First NNRTI
approved
First once-daily
ARV approved
First boosted
PIapproved
1 2 1
www.emea.europa.eu/; http://www.fda.gov/bbs/topics/NEWS/2006/NEW01408.html
2007
2
First integrase inhibitor approved
First CCR5 antagonist approved
ARV, antiretroviral; CCR, chemokine receptor (C–C motif); NNRTI, non-nucleaoside reverse transcriptase inhibitor; PI, protease inhibitor
First HAART fixed-dose
combination approved
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We have better and more tolerable therapy
It appears we have:
• Less short term toxicity-diarrhoea, dyslipidemia
• Less long term toxicities such as lipodystrophy
• Better formulations– easier to take
– lower pill burdens-one pill once a day
– no refrigeration
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So why should HIV-Infected Patients Be Offered Earlier Treatment?
• Better tolerability and less toxicity of therapy
• Better chance of normalising CD4 count
• Lower risk of developing resistance
• Fewer OIs and deaths
• Preventing Non-AIDS defining events
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Don't wait until its too late
• In Patients presenting with OIs including tuberculosis it is important to start ARVs as soon as is practicable
• Toxicity, adherence and IRIS are important but outweighed by the morbidity and mortality in those that don't start HIV treatment
Dean et al AIDS. 2002;16;75-83 ,Lawn s et al CROI 2007 abstract 81, Zolopa A, et al. CROI 2008. Abstract 142.
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Once on therapy then Don't Stop!
The SMART study
Plus DART and Trivacan
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New Classes of drugs
Integrase inhibitors-Raltegravir
CCR5 antagonists- Maraviroc
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HIV-1 lifecycle
RT
Provirus
ProteinsRNA
DNA
RNA
DNA
DNA
RT
Viral protease
Reversetranscriptase
RNA
RNA
DNA
DNA
DNA
Entry
Integrase
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What is the place of new drugs in HIV treatment experienced patients?
A new Paradigm
Now we should aim for viral load undetectability
The likelihood of reaching an HIV-1 RNA level lower than 50 copies/mL is highest if more than 2 active drugs are in a regimen and a new class is used
Hammer et al. JAMA (2006) 296:827–43
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What is the place of new drugs in HIV Naive Patients?
• CCR5 inhibitors- Maraviroc didn't match up to Efavirenz but some Virological failures driven by the innacuracy of the tropism test used
• Integrase plus nucleosides? -Good 96 week data but need large comparative study
• Nucleoside sparing- boosted PI and integrase?• Trial planned in Europe by NEAT network using an
efavirenz, tenofovir, FTC reference arm to look at these 2 latter approaches
• Also studies are underway to evaluate 2 NNRTIs as well
Hammer et al. JAMA (2006) 296:827–43