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

The early days of HIV care Diagnosis of HIV infection was clinical Emphasis on care was on:  Management of opportunistic infections and cancers Early diagnosis Prompt and effective treatment  Psychosocial support Palliative care Minimise stigma  Health education on prevention

The early HIV related Guidelines First international guidelines by WHO and CDC  Targeting resource limitted settings  AIDS case surveillance definition  October 1985, Bangui, CAR  Public Health experts + CDC representation  Revised 1994 HIV serology optional – when available

The early HIV related Guidelines Other guidelines followed including:  WHO clinical staging system  Management of opportunistic infections  HIV prevention On PMTCT At the work place  Home care and counseling  ART IAS-USA WHO

“Slim Disease”/Wasting

Kaposi’s sarcoma

Kaposi’s sarcoma before and after chemotherapy

Early days of antiretroviral therapy AZT and monotherapy  Premature termination of the studies Toxicity and short-lived response Dual therapy of NRTIs  d4T, ddI, ddC  Better than monotherapy but not good enough Considered suitable for sub-Saharan Africa Triple therapy and the PIs – 1996  The basis of the current ART strategies

Development of International Guidelines Generated by a panel of experts in the relevant fields  Regional representation Often evidence or consensus based or both  Published research  Clinical or field experience Subject to regular review  When new evidence become available

Major contentions of ART guidelines When to start ART  Early vs delayed start  What criteria to use Clinical + CD4 count or viral load or both WHO or CDC staging – for adults and children What to use as first line therapy  Triple nukes and which ones  Use of PIs as first line

HIV-1 lifecycle RT Provirus Proteins RNA DNA RNA DNA RT Viral protease Reverse transcriptase RNA DNA Entry Integrase

Continued Evolution of HAART 25 drugs and counting First protease inhibitor (PI) approved 1995 First fixed- dose (triple) combination approved First fusion inhibitor approved Number of new approved ARV agents (1996–2007) First fixed- dose (dual) combination approved First NNRTI approved First once-daily ARV approved First boosted PI approved 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

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

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

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 Abstract 142.

Once on therapy then Don't Stop! The SMART study Plus DART and Trivacan

New Classes of drugs Integrase inhibitors-Raltegravir CCR5 antagonists- Maraviroc

HIV-1 lifecycle RT Provirus Proteins RNA DNA RNA DNA RT Viral protease Reverse transcriptase RNA DNA Entry Integrase

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

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