An early START: major study finds early HIV treatment is best

HIV Australia | Vol. 13 No. 2 | July 2015

Bill Whittaker

BILL WHITTAKER reflects on the long debate about when to start HIV treatment, at a pivotal moment in the HIV response.

A major development in the ‘when to start’ HIV antiretroviral treatment debate was the announcement in May 2015 that a large randomised controlled clinical study called START¹ has been stopped early after the study’s independent data and safety monitoring board (DSMB) found compelling evidence that the benefits of starting antiretroviral treatment immediately at CD4+ cell counts above 500 cells/mm3 outweigh the risks.² ³

The findings support offering HIV treatment to all people with HIV, regardless of CD4+ cell count.

For many working in the HIV field, this is a significant announcement, as the question of when is the best time to start antiretroviral treatment has been the focus of much research and debate since the first antiretroviral drugs became available over 25 years ago.

At face value, it seems obvious that if you have a life-threatening disease and there are treatments available, you would start treating right away. However, that presupposes that the treatments work long-term and that they are tolerable and affordable. For HIV treatment, the reality is that it has taken decades to develop today’s modern antiretroviral drugs.

It has also taken decades of research to gain essential knowledge about HIV disease and its consequences, which provide the foundations on which effective antiretroviral drugs can be developed.

The START study announcement highlights the long and remarkable story of antiretroviral treatment development – and the debate about when is the best time to start using treatment.

This goes back to zidovudine (AZT), the first antiretroviral, which became available in Australia in the late 1980s.

AZT provided a remarkable breakthrough. Finally, several years after the first reports of AIDS,⁴ ⁵ ⁶ a treatment offered hope. However, enthusiasm about AZT was soon tempered by the reality that it provided only short-term benefit to people with advanced HIV disease.

Also, AZT had serious toxicities and drug resistance developed quickly. Added disappointment came later from the findings of the UKFrench Concorde⁷ clinical trial, which cast doubt on the value of using AZT earlier in people with symptom-free HIV disease.

After AZT’s release, antiretroviral drug development evolved slowly over the early 1990s – a time where AIDS-related deaths and illness were at their peak in Australia and many other countries.

The relatively few new drugs developed in this period had similar shortcomings to AZT.

Based on these limitations, it seemed prudent to reserve antiretroviral treatment for people with more advanced symptomatic disease and/or lower CD4+ cell counts (CD4+ cell counts help measure immune system health), typically using a threshold of around 200 to 500 CD4+ cells to consider starting treatment.

A breakthrough occurred in 1994, when two major clinical trials⁸ ⁹found that combining antiretroviral drugs delivered a better clinical outcome than using drugs one by one (monotherapy).

This finding heralded the era of ‘combination HIV treatment’, which called for antiretroviral drugs to be combined to maximise their impact and help reduce the problem of antiretroviral drug resistance.

As noted earlier, progress in developing better antiretroviral drugs is obviously linked to gaining knowledge about HIV and the course of HIV disease.

By the middle of the 1990s, much had been learned about HIV and its prevention and treatment. However, there were also big gaps in knowledge, and this included not having definitive evidence to guide decisions about when to start antiretroviral treatment in early HIV disease.

The approach of deferring antiretroviral treatment was challenged by Dr David Ho of the Aaron Diamond Institute (NYC) in 1995 when he famously wrote that it was time to ‘Hit HIV, Early and Hard’.¹⁰

Ho and colleagues proposed that there was no latency in HIV disease and that the HIV virus caused damage from very early HIV infection onwards. Ho went further and predicted that it may actually be possible to eradicate HIV if potent drugs were used early in the course of HIV infection.

Around the same time, a powerful new class of HIV antiretrovirals called ‘protease inhibitors’ became available, along with better diagnostic tests (such as viral load testing to measure how much HIV replication is occurring in the body).

There was tremendous excitement over these advances, with the International AIDS Conference in Vancouver in 1996 now synonymous with their introduction.

As noted by Dr Kevin DeCock of the US Centers for Disease Control and Prevention (CDC), ‘Conference delegates were stunned by presentations of individual case histories of patients dying of AIDS who were rescued by ART, colorfully referred to as “the Lazarus effect”.’¹¹

However, these more effective antiretrovirals, including the first protease inhibitors, still carried with them various limitations, including complex dosing schedules and often debilitating toxicities and side effects.

A significant number of people continued to experience antiretroviral treatment failure during this time.

A caution around early use of treatment arose in 2000, when Professor Andrew Carr and colleagues from Australia identified a syndrome in HIV patients involving body shape changes, lipid abnormalities and other toxicities, which were likely linked to protease inhibitor drugs.¹² ¹³

Later, these abnormalities were also linked to some other older antiretroviral drugs and it was also found that HIV itself was a likely contributor to the syndrome.

HIV treatment guidelines of the time reflected the limitations of some protease inhibitors and other antiretrovirals, and they generally supported clinicians and patients using a 200 to 500 CD4+ cell count range as the threshold for starting HIV treatment.

Relatively few people commenced treatment at high CD4+ cells above 500.

Notwithstanding the limitations of HIV antiretrovirals, their effect on disease progression, sickness and death has been absolutely dramatic from the mid-1990s onwards.

HIV-related mortality and morbidity rates have plummeted in many countries, including Australia. Despite predictions that HIV treatment could never be successfully delivered and sustained in lower income countries, treatment success stories emerged, including in Africa where the burden of HIV is greatest.

However, treatment in developing countries was (and still is) often restricted to people with very advanced HIV disease, resulting in many examples where illness and death could have been avoided through earlier treatment access.

Today, we have a very clear picture of what constitutes ‘gold standard’ HIV antiretroviral treatment – where antiretrovirals need to be potent, easy to take, have minimum side effects and be affordable.

Over the past 15 years, a host of new drugs in different drug classes have been successfully developed in line with this ‘gold standard’.

This focus continues today, with various novel antiretroviral treatments in development, as well as single tablet, once-daily formulations of HIV antiretrovirals, some of which are already available through Australia’s Pharmaceutical Benefits Scheme (PBS).

As better antiretroviral drugs have become available, as well as long-term data demonstrating their safety and effectiveness, debate has continued about the optimum time to use them.

Some clinicians believe that the ‘when to start’ treatment question is already answered based on expert opinion and various studies finding health benefits in not delaying treatment.

Other eminent clinicians have not agreed, citing for example a lack of evidence for using antiretrovirals in asymptomatic HIV-positive people with higher CD4+ cell counts (e.g. a 500 CD4+ cell count or higher).

Community advocates have also had differences of opinion about when to start treatment based on their interpretations of the evidence.

During 2008, enthusiasm grew for a clinical study to answer – once and for all – the question of when to start HIV treatment, and to do this via a large multi-centre randomised clinical study in order to provide the highest level of evidence.

It was decided that the study would be conducted by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)¹⁴ with funding from the US National Institute of Allergy and Infectious Diseases (NIAID).

Activists, clinicians and scientists worked on the study design and set up a network of coordinating centres in several countries, including Australia.

It should be noted that some clinicians and activists questioned whether such a large investment in a major study to answer this question was warranted, and whether it would be overtaken by other scientific developments and not be completed.

The START (‘Strategic Timing of Antiretroviral Treatment’)¹⁵ study got underway in early 2009 with the aim of defining the optimal time for people with HIV to begin antiretroviral treatment.

The study enrolled healthy, asymptomatic, HIV-positive people whose level of CD4+ cells exceeded 500.

The primary objective of the study was to determine whether starting antiretroviral treatment immediately would lead to a lower risk of AIDS, other serious illnesses or death compared to waiting until a person’s CD4+ cell count fell to 350 cells.

The study was scheduled to end in 2016, subject to regular review by a data and safety monitoring board (DSMB). Australian involvement in START was led by Professor Sean Emery and colleagues from the Kirby Institute, via a network of clinicians around Australia.

Community involvement was a particular feature of START and of the INSIGHT Network, with the National Association of People Living with HIV Australia (NAPWHA) being involved in the study from its beginning in 2009, and NAPWHA’s CEO, Jo Watson, serving on the INSIGHT international coordinating group.

Over 100 Australians volunteered to be part of START, and along with 4,500 other participants from around the world, these individuals deserve enormous credit for volunteering for the study and participating in it over several years.

The HIV treatment and prevention field has continued to evolve since START got underway in 2009, with a growing body of scientific evidence and expert opinion favouring starting HIV treatment early, as soon as the patient is ready.

Research on the impact of treatment on HIV transmission provided a major advance in prevention, with the HPTN 052 study¹⁶(released in 2010) demonstrating that antiretroviral treatment reduced HIV transmission from an HIV-positive partner to an HIV-negative one by at least 96% in heterosexual couples.

The PARTNER study¹⁷ (presented in 2014) found a similar result among men who have sex with men. The TEMPRANO study¹⁸(presented in 2015) lent support to the view that the threshold for starting treatment should shift from a CD4+ cell count of 500 to whenever the patient is ready to start.

Reflecting these and other developments, most HIV treatment guidelines today recommend that all people with HIV should be offered antiretroviral treatment, irrespective of their CD4+ cell count, while also noting that the level of evidence for such a recommendation (for people with higher CD4+cell counts) is largely based on non-randomised studies and expert opinion.

In Australia, we follow the US Department of Health and Human Services HIV Treatment Guidelines¹⁹ which were the first guidelines to recommend (in 2013) that antiretroviral treatment be offered to all people with HIV who are ready to start treatment, irrespective of their CD4+ cell count.

The question of when is the best time to start antiretroviral treatment was addressed in a 2014 communiqué from the Australian Society for HIV Medicine (ASHM), which proposes the principle that all people with HIV should consider commencing treatment, while noting that the strength of evidence varies.²⁰

Treatment targets recently set under Australia’s National HIV Strategy²¹ and endorsed by all Australian Health Ministers call for antiretroviral treatment coverage of 90% among people with HIV, in recognition of the individual and public health benefits of being on antiretroviral treatment.

As stated previously in this article, on May 2015 the START study was stopped²² over a year early, after the DSMB for the study found compelling evidence that the benefits of starting antiretroviral treatment at CD4+ cell counts above 500 cells outweigh the risks.

Specifically, the DSMB found that over an average followup of three years, the risk of AIDS, other serious illnesses or death was reduced by 53 percent among those in the early treatment group compared to those in the deferred treatment group.

These are the headline findings of START, but we can expect START to be a study that ‘keeps on delivering’, including through a number of important sub-studies looking at other aspects of HIV clinical management.

It is likely that findings from START and the continued analyses of data from the study will provide many valuable insights into HIV treatment and prevention efforts in the years ahead.

Many of us are looking forward to reading the full published START study results, which should become available in coming weeks.

However, there are three key messages from START that should be acted on without delay and disseminated widely:

If you are at risk of HIV, then get tested and test often.
If you have HIV and aren’t taking HIV treatment, you are recommended to consider starting treatment immediately.
If you are a doctor caring for people with HIV, you should discuss the implications of the START study with patients as early as possible.

There is no doubt that the results from START are a very important development in the global response to HIV.

These study results will influence how HIV is treated and prevented around the world, in both developed and developing countries.

It is critically important that all Australian governments and non-government organisations get the message out now about START’s findings and its implications for HIV treatment and prevention.

Australia should use our new National HIV Strategy to help mobilise the clinical workforce and affected communities around early uptake of HIV treatment.

While there will likely be some differences of opinion about START and its impact, everyone should agree that it is an immensely valuable study in confirming, via a randomised controlled clinical study, that the approach of treating early which is now being implemented in many countries, including Australia, is the best approach to treating HIV.

For many people with HIV and their doctors, the clarity of the START findings will help confirm their choices about starting HIV treatment and empower governments, communities and health professionals to redouble efforts towards the goal of ending HIV and AIDS in every country.

References

1 The purpose of the START study was to determine whether immediate initiation of antiretroviral treatment (ART) is superior to deferral of ART until the CD4+ cell count declines below 350 cells/mm3 in terms of morbidity and mortality in HIV infected persons who are antiretroviral naïve with a CD4+ cell count above 500 cells/mm3.

For information on the START study protocol see: International Network for Strategic Initiative in Global HIV Trials (INSIGHT). (2010, 25 October). Strategic Timing of AntiRetroviral Treatment (START). INSIGHT PROTOCOL 001. START DAIDS Document ID #10619. Retrieved from: insight.ccbr.umn.edu

2 The Kirby Institute. (2015). Results from world-first clinical trial support early treatment for HIV. Media release. The Kirby Institute, UNSW Australia, Sydney. Retrieved from: kirby.unsw.edu.au

3 The Kirby Institute. (2015b). Questions and Answers – The START HIV Treatment Study statement. The Kirby Institute, UNSW Australia, Sydney. Retrieved from: kirby.unsw.edu.au

4 Centers for Disease Control and Prevention (CDC). Pneumocystis pneumonia — Los Angeles. Morbidity and Mortality Weekly Report (MMWR), 30, 250–2. Retrieved from: www.cdc.gov

5 Gottlieb, M., Schroff, R., Schanker, H., Weisman, J., Fan, P., Wolf, R., et al. (1981). Pneumocystis carinii Pneumonia and Mucosal Candidiasis in Previously Healthy Homosexual Men — Evidence of a New Acquired Cellular Immunodeficiency. N Engl J Med., 1305,1425–1431. doi: 10.1056/NEJM198112103052401

6 First media report available at: www.nytimes.com

7 Concorde Coordinating Committee. (1994). Concorde: MRC/ANRS randomised doubleblind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Concorde Coordinating Committee. The Lancet, 343(8902), 871–881.

8 Delta Coordinating Committee. (1996). Delta: a randomised double-blind placebo-controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Delta Coordinating Committee. The Lancet 348, 283–291.

9 Hammer, S., Katzenstein, D., Hughes, M., Gundacker, H., Schooley, R., Haubrich, R., et al. (1996). A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200–500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. N Engl J Med.,335(15), 1081–1090.

10 Ho, D. (1995). Time to Hit HIV, Early and Hard. N Engl J Med.,333, 450–451.

11 See more at: blog.aids.gov

12 Carr, A., Samaras, K., Burton, S., Law, M., Freund, J., Chisholm, D., et al. (1998). A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS, 12(7), F51–8.

13 Carr, A., Cooper, D. (1998). Lipodystrophy Associated with an HIV-Protease Inhibitor. N Engl J Med., 339, 1296. doi: http://dx.doi.org/10.1056/NEJM199810293391806

14 See: insight.ccbr.umn.edu/index.php

15 INSIGHT. (2010, 25 October). op cit.

16 See: www.hptn.org/research_studies/hptn052.asp

17 Rodger, A., Bruun, T., Cambiano, V., Vernazza, P., Estrada, V., Van Lunzen, J., et al. (2014). HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER study. Presentation delivered at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014), Boston. Abstract 153LB.

18 Danel, C., Gabillard, D., Le Carrou1, J., Anglaret, X., Moh,R., Eholie, S., et al. (2015). Early ART and IPT in HV-infected African adults with high CD4 count (Temprano trial). CROI 2015, Seattle. Abstract 115LB.

19 The US Department of Health and Human Services (DHHS) Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults together with Australian commentary provided by ASHM (Australasian Society of HIV Medicine) are available at: http://arv.ashm.org.au

20 Australasian Society of HIV Medicine (ASHM). When to start antiretroviral therapy in people with HIV. ASHM, Sydney. Retrieved from: arv.ashm.org.au

21 Australian Government Department of Health. (2014). Seventh National HIV Strategy 2014–2017. Commonwealth of Australia, Canberra. Retrieved from: www.health.gov.au

22 See: The Kirby Institute. (2015). op cit.

Bill Whittaker AM is Special Representative for the National Association of People with HIV Australia (NAPWHA) and a former President of the Australian Federation of AIDS Organisations (AFAO).

He is one of the architects of Australia’s response to HIV/AIDS and has worked in HIV advocacy, policy and strategy for more than 25 years.