Antiretroviral therapy : research , rollout and resistance

Antiretroviral therapy has revolutionised the management of human immunodeficiency virus (HIV). Advances in research leading to the development of combination antiretroviral therapies (ARTs) have led to significant decreases in AIDS related morbidity and increases in life expectancy for individuals with access to treatment. The goal of ‘getting to zero : zeroAIDs relateddeaths’now iswithin reach.Globally nearly 10million people have access to ART; however, further rollout efforts are required to reach the 34million people livingwithHIVsustainablyover the longterm.Changing paradigms see a broader scope for ART with a push towards earlier initiation, and even pre-exposure prophylaxis, with public health goals of preventing new infections. In Australia, collaborative research efforts, bipartisan political will and subsidised medication costs have allowed around 13000 people to be maintained on antiretroviral therapy. Despite this, the challenges of continuous lifelong suppressive therapy remain, as currently there is no cure. Poor adherence can lead to disease progression and drug resistance, limiting future treatment options. Antiretroviral resistance in Australia appears to have been stable, but changing epidemiology and evolving viral subtypes may impact these rates. This article will reflect on the advances in antiretroviral research, rollout and resistance in our region.


David A Cooper
The Kirby Institute Wallace Wurth Building UNSW Australia Sydney, NSW 2052, Australia Email: dcooper@kirby.unsw.edu.auAntiretroviral therapy has revolutionised the management of human immunodeficiency virus (HIV).Advances in research leading to the development of combination antiretroviral therapies (ARTs) have led to significant decreases in AIDS related morbidity and increases in life expectancy for individuals with access to treatment.The goal of 'getting to zero : zero AIDs related deaths' now is within reach.Globally nearly 10 million people have access to ART; however, further rollout efforts are required to reach the 34 million people living with HIV sustainably over the long term.Changing paradigms see a broader scope for ART with a push towards earlier initiation, and even pre-exposure prophylaxis, with public health goals of preventing new infections.
In Australia, collaborative research efforts, bipartisan political will and subsidised medication costs have allowed around 13 000 people to be maintained on antiretroviral therapy.Despite this, the challenges of continuous lifelong suppressive therapy remain, as currently there is no cure.
Poor adherence can lead to disease progression and drug resistance, limiting future treatment options.Antiretroviral resistance in Australia appears to have been stable, but changing epidemiology and evolving viral subtypes may impact these rates.This article will reflect on the advances in antiretroviral research, rollout and resistance in our region.
Australia has benefitted from early access and rollout of ART, and now has one of the highest treatment rates in the world, with around 50-70% of those diagnosed receiving treatment, and 85-95% of these with a suppressed viral load (see Figure 1) 1 .
Progression to AIDS has been halved, deaths have fallen by 80%, and life expectancies approaching the general population can now be expected [2][3][4] .
Currently available ART targets five key pathways of the HIV life cycle (see Figure 2 in PI resistance 11 .In Victoria and NSW, rates of transmitted drug resistance have since remained stable at 10-16% when last analysed [11][12][13] .Since then, there appear to be some shifts in the epidemiology of HIV in South Australia, which comprises 4% of the national HIV burden, with an increased incidence of non-B subtypes now accounting for almost half of new diagnoses 14 .They tend to occur in females born overseas, acquired overseas through heterosexual transmission, and reflect increasing migration from high prevalence countries 15,16 .Non-B subtypes may have different rates of disease progression, and treatment responses, as transmitted subtype specific polymorphisms can lead to different patterns of secondary resistance.However, the locally predominant subtype B mainly occurs in men who have sex with men and still comprises the majority of new infections in Australia overall.Ongoing surveillance of changing subtypes and patterns of resistance, particularly in higher burden regions of Australia is imperative.
In other regions, such as Asia and Africa, the availability of resistance testing is more limited and virological failures rates due to resistance are much more varied 7 .In the setting of failure of a first line regimen in resource limited countries, a recent Australian led study has demonstrated that a novel combination of a boosted PI and integrase inhibitor is non-inferior to the WHO recommended nucleotide and PI based regimen 10 .While providing much needed clinical trial data for the one million people in low to middle income countries requiring second line treatment, this novel regimen currently is not cost effective in some of these countries where ART is provided through donor or publicly funded programmes.
The scope for ART is broadening to settings beyond treatment of the individual living with HIV.ART for post exposure prophylaxis, while not TGA licensed for this indication, has been available in Australia for high risk occupational and non-occupational exposures.Additionally, non-prescribed informal use for recreational or pre exposure prophylaxis has been reported in HIV negative people, sometimes during high risk behaviour 17,18 .
Treatment paradigms are shifting from being solely focused on the Studies such as these breathe extended life into currently available ARVs.
This broader public health approach to treatment must be balanced The development of ART has led to significant improvements for individuals living with HIV, and could lead to an AIDS free generation.On a community level, the rollout of ART has had significant impacts on transmission and rates of new infections.The current goal of 'getting to zero' requires further ART rollout efforts and healthcare support spending from a shrinking funding pool.
Renewed political will, financial commitment and innovative solutions are needed to bridge this gap.

Figure 1 .
Figure 1.Observed and predicted proportions of Australian HIV Observational Database patients with detectable viral load 1997-2009.Image obtained from Law et al.J. Int.AIDS Soc.2011; 14: 10 and published under the Creative Commons Attribution 3.0 Unported (CC BY 3.0) license.
with the benefits of treatment for the individual patient.Despite all the advances in antiretroviral treatment over the years, one of the most fundamental questions remains unanswered: when to start treatment?The 2013 WHO guidelines have been edging towards earlier treatment, and now recommend ART initiation at CD4 count >350 and 500 cells/mm 3 regardless of clinical stage.When faced with an individual patient, the decision to start earlier must be balanced against a commitment to taking a lifelong medication.The Strategic Timing of AntiRetrovirals Trial (START) due for completion in December 2015 aims to answer this question (NCT00867048).