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

cancersEarly diagnosisPrompt and effective treatment

Psychosocial supportPalliative careMinimise stigma

Health education on prevention

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

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

“Slim Disease”/Wasting

Kaposi’s sarcoma

Kaposi’s sarcoma before and after chemotherapy

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

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

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

HIV-1 lifecycle

RT

Provirus

ProteinsRNA

DNA

RNA

DNA

DNA

RT

Viral protease

Reversetranscriptase

RNA

RNA

DNA

DNA

DNA

Entry

Integrase

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

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 2008. 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

ProteinsRNA

DNA

RNA

DNA

DNA

RT

Viral protease

Reversetranscriptase

RNA

RNA

DNA

DNA

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