Issues that divide expert opinion: when to start, HIV and ageing and the impact of HIV on life expectancy
Simon Collins, HIV i-Base
The Glasgow programme included overviews of three key aspects of HIV that still divides experts. This included when to begin ART, the overlapping complexity of HIV and ageing and the impact of both these issues on life expectancy.
The range of views held on each subject can make these discussions an unsettling experience for a patient who just wants to do the best thing for their health and who is faced with conflicting expert opinions.
- Should everyone start treatment or is greater caution and additional data warranted, on a population level, and especially for those with highest CD4 counts?
- Does HIV drive earlier and more complex ageing or can the differences previously reported be explained by use of inappropriate control groups and modifiable lifestyle factors?
- Is life expectancy for HIV positive people approaching that of HIV negative people, or are we still falling 10-20 years short because of HIV itself or the complex demographics of HIV cohorts?
If this is confusing for people diagnosed early when their CD4 count is still high and who have good access to treatment, it is more confusing for people with more complex histories. These questions are more than just an academic debate and the overlapping connections between these three subjects made for interesting discussions at the conference.
When to start: asap or not so fast?
A few years ago, when the international START study was being planned, feedback from UK doctors argued for the CD4 threshold for early treatment to be 450 as there was a concern that setting this at 500 would be make the study impossible to enrol. Even 450 was expected to be a challenge given the consensus to defer until treatment was “really needed”.
A lot has changed since then. There has been increasing attention given to concerns from unsuppressed viraemia and the associated immune inflammation. There is also greater confidence that ART is protective of serious non-AIDS events including cardiovascular, renal and hepatic disease and some cancers, rather than driving morbidity due to side effects. Finally, the reduced infectiousness demonstrated in HPTN-052 proves the potential of ART to reduce onward transmission.
In Glasgow, one of the first sessions included a debate on the timing of ART on a population level, with the extreme viewpoints of either universal treatment on diagnosis compared to deferring until the CD4 count reaches 350 cells/mm3.
Michael Saag, fromUniversity of Alabama, (and a member of the US DHHS guideline panel) argued that the above benefits are sufficient in themselves to move to a policy of treatment after diagnosis, irrespective of CD4 count. 
This is broadly recommended in the US DHHS guidelines but expressed more extremely by the 2012 IAS-USA guidelines. Both panels believe that the complications of current treatment are sufficiently manageable for the difference of an average of 40 rather than 35 lifetime years of treatment to be negligible, and that public health will benefit from reductions in population viral load. While data from randomised studies are not available for people with higher CD4 counts, Saag argued that cohort data suggests that earlier treatment, at the least in the short-term, does not indicate significant harm. Also, for some doctors, the increasing concern of the long-term implications from uncontrolled HIV viral replication prior to starting treatment, and to a lesser extent, even residual viraemia on treatment, has become such a convincing concern that they see withholding treatment, even from people with the highest CD4 counts, as approaching medical negligence.
To counter this interpretation of the current evidence, Jens Lundgren, fromthe University of Copenhagen, (a member of the EACS guideline panel and co-chair of the START study) argued that a move to universal treatment was a sufficiently important public health policy for this to need to be driven by rigorous evidence that personal benefits outweigh the risks for patients with CD4 counts higher than 350 and especially when higher than 500.  The need for this to come from randomised studies is important because so far, large cohort studies have reported contradictory results for these patients. The lack of evidence from studies that were designed to look at the potential harm from earlier treatment (this not a strength of cohort studies) has lead to a reliance for this aspect of the guidelines, on expert opinion, which is universally accepted as the least reliable evidence base for treatment recommendations.
One caution that should temper any rush to universal treatment at higher CD4 counts, comes from data showing that outside the context of clinical studies, 10-30% of patients do not achieve optimal viral suppression on their first combinaton, increasing the likelihood of drug resistance, potentially years before there was a clinical need for treatment. Also, while tolerability with todays treatment has steadily improved, potential toxicity may be reduced further in future treatments.
This raises a reasonable caution against everyone starting treatment at CD4 >350 when the absolute risk of HIV related events is already very low, especially given that historically, earlier treatment based on expert opinion has invariably proven to be wrong. The equipoise supported by the current data is especially important to emphasise for people currently in the START study.
This large international study will enroll the last of its 4000 proposed participants earlier in 2013, all with CD4 counts higher than 500 cells/mm3 at baseline. Following randomisation to either immediate ART or deferring until CD4 counts reach 350, results are expected by 2016, or earlier if the differences between the two arms are strikingly different.
Participants currently in the deferred arm of the START study, should remain confident and supported by data from large European cohorts showing that the absolute risk for events occurring while their CD4 count is between 350 and 500, is unlikely to very be different from if they started at 500.
Similarly, participants in the immediate arm of START should be reassured that cohort data support the low risk of complications from earlier ART, but that this is dependent on maintaining an undetectable viral load, itself related to careful adherence. Also, that a lower quality of life should not become the price for reducing community viral load, though both are challenging to measure: treatment is easy to modify or switch if the first combination is difficult to tolerate.
Until the START study produces results, individuals with high CD4 counts should be supported if their preference is to start treatment, whether they are doing this for their own or their partner’s health. HIV treatment is highly individual though and this decision will be right for some but not for others.
For patients outside the START study,the drive for treatment as prevention is only likely to increase between now and 2016 – irrespective of the clinical impact of earlier treatment – it is important to keep a clear distinction between population level benefits and personal health benefits when individualising the decision to start treatment.
HIV and ageing: a clinical concern or confounded by inappropriate controls?
The impact and association of HIV and ageing was the second topic discussed in Glasgow upon which experts hold diverse opinions. Again, these views impact on clinical decisions, including whether to start earlier treatment. At one extreme, the question of whether HIV directly contributes to significantly faster ageing and increased comorbidities, even in the context of stable treatment – or whether previous reports of early or premature ageing can be explained by the difficulty of identifying appropriate HIV negative control populations?
Several important research groups have contributed to this debate. In July 2012, a supplement to JAIDS, published to coincide with the IAS conference in Washington DC, reviewed four key areas on HIV and ageing. This included the mechanisms for functional decline in innate and adaptive immunity in HIV positive people, the evidence for increases in some biomarkers associated with both HIV and ageing, the role of comorbidities and the diverse behavioural and socio-economic factors that make the HIV positive population such a complex demographic group. While acknowledging that ART increased life expectancy to 70 years, the paper focused on why this hasn’t normalised to HIV negative levels. It also proposed key research challenges that need to be prioritised in order to answer these questions. 
At CROI 2012, Amy Justice, from the Veterans Affairs Healthcare System (and a co-author of the JAIDS review), emphasised the difference between the potential role of HIV in both “accelerated ageing” (where comorbidities might be occuring at an earlier age) and “accentuated ageing” (where they occur at a higher rate) – and that these effects are not mutually exclusive. This oral presentation also reported the data showing how the lack of adjustment for the younger age of HIV positive compared to general population cohorts, can explain studies that previously suggested HIV positive people might age 20-30 years earlier than HIV negative people. 
In Glasgow, Peter Reiss, from the University of Amsterdam, the Netherlands (a co-author of the JAIDS supplement on ageing and a member of both EACS and IAS-USA guideline panels), presented an overview on the potential mechanisms for how HIV might negatively interact with comorbidity and ageing. 
As background, many Western epidemics are approaching the time where more than half the HIV positive population will be older than 50 years old, and that the exponential increase in chronic conditions commonly identifies age as the single strongest risk. This includes cardiovascular, renal, pulmonary and hepatic disease, bone health, neurocognitive function, diabetes and frailty.
Concerns about HIV and ageing are especially focused on people who initiated treatment at lower CD4 counts, who are less likely to achieve CD4 counts >500 cells/mm3 on treatment, often due to late presentation. Adjustment for the younger age of HIV positive cohorts has explained earlier reports that HIV positive people developed non-AIDS cancers at an earlier age.  However, several studies have also reported that there is greater use of concomitant medications at an earlier age (polypharmacy) – though this may be driven by the better care and more frequent monitoring that HIV positive people receive. 
Prior to treatment, immunologic disruption, HIV and CMV replication, the loss of mucosal gut integrity and microbial translocation, all contribute to a heightened state of immune activation. Although greatly reduced on ART, residual activation may maintain an inflammatory state that continues to increase the risk of fibrotic and coagulant states and these are associated with higher comorbidites. The degree to which this accelerates a healthy ageing process, that by definition involves changes in immune function and tissue and cellular structure, is for research to establish.
So, however compelling and plausible the concerns from inflammation appear, Reiss emphasised that these concepts currently remain a hypothesis that needs to be either proven or refuted – and that this is already the focus of several large studies. Until then, lifestyle choices (including diet, exercise, quitting smoking) may be able to ameliorate many of these additional risks factors that contribute to comorbidity in HIV positive people, just as they do in the general population. And that the issue of HIV and ageing, will become increasingly important globally.
Life expectancy: models for the ultimate outcome
The JAIDS supplement on ageing referred to above, while acknowledging that ART dramatically extends life, also included the following provocative sentence in the opening paragraph of the reports executive summary: “On average, a 20-year old initiating ART may already have lost one-third of the expected remaining years of life compared with demographically similar HIV-uninfected populations” , based on a study by the Antiretroviral Therapy Cohort Collaboration (ART-CC) published in 2008. 
The conference in Glasgow included a session on HIV and life expectancy. The first of three presentations was an overview by Caroline Sabin from University College London.  Given this ultimate outcome is such an important concern, it is notable that this may have been the first time this subject has been given a dedicated session in a conference programme.
Life expectancy, as an important indicator of health, is sometimes referred to from birth, but in the context of HIV is more often presented as additional life years in relation to age at diagnosis/infection. Other measures include:
- years of life lost,
- potential gains in life expectancy,
- excess mortality (per 1000 patient years), and
- standardised mortality ratios (SMR) compared to an age and sex matched general population control group.
With the durability of ART, several research groups have reported increasing levels of life expectancy, that now approach that of a similarly matched HIV negative general population. These include models from cohort studies (including ART CC and UK CHIC) estimating an additional 45-49 years of life expectancy for someone diagnosed at age 20 in a Western country with good access to care. [9, 10]
A more recent model, published in AIDS earlier this year, extended life expectancy to 75 years (95%CI: 68-77) for a gay man diagnosed in 2010 at age 30 with a CD4 count of 430, losing approximately 7 years of life due to HIV. Life expectancy dropped to 71, if the CD4 count was 140 on diagnosis, losing approximately 10 years. 
These studies are broadly similar in reporting that the factors associated with longer life expectancy include calendar year, higher CD4 count, suppressed viral load, earlier presentation, fewer coinfections and in non-IDU populations. Adjustment for lifestyle factors may also account for the majority of the differences between HIV positive and general population estimates (approximately 8 out of the 11 year differences in a US study). Gender, race, injecting drug use (IDU), late presentation and stopping treatment were all associated with greater differences. 
An analysis from more than 80,000 HIV positive people in the European COHERE cohort collaboration in 2012 reported that IDU (16% of the cohort) and low CD4 count explained most of the differences in life expectancy between HIV positive and HIV negative groups. 
Mortality rates became similar to those of the general population once CD4 counts reached >500 on treatment in non-IDU men [SMR 0.9; 95% CI 0.7-1.3], and in women after three years at this level (SMR 1.1, 95% CI 0.7-1.7). Of note, although mortality rates increased with age, excess mortality relating to HIV status significantly reduced with older age, with HIV positive MSM older than 60 years who haven’t had a previous AIDS diagnosis achieving reduced SMR mortality compared to the matched general population.
However, mortality rates for the whole cohort remained four times higher than the general population (SMR for men: 3.8, for women: 7.4) at 1.2/100 person-years. Mortality for IDU was 13.1 times higher (95% CI 10.5–16.5) than in the general population, and by gender, results were 11.7 higher (95% CI 9.4–14.7) in men and 22.7 times (95% CI 18.0–28.7) higher in women. Mortality also remained elavated in IDU even with CD4 >500 (SMR 5.7; 95% CI 4.2–7.8). Although duration on treatment helped, even after five years, rates remained significantly increased.
Take as a whole, this returns the focus for ageing and life expectancy studies back to the difficulties of finding appropriate general population control groups. Within the UK, for example, average life expectancy can vary by 20 years depending on geographic region and even within London post codes can vary by greater than 10 years. Modifiable lifestyle factors are important, irrespective of HIV status.
Across all these studies, modelled estimates are dependent on extrapolating relatively short-term data. They may underestimate life expectancy by not accounting for future advances in treatment (think of the cure research) and overestimate it by not accounting for currently unknown future complications (whether from ART toxicity, drug resistance or the role of inflammation). Sabin summarised that life expectancy remains poorly explained for children and that the ageing population will clearly having important implications for the global epidemic.
These three issues are closely related, but luckily the middle ground for most people reduces the urgency of each extreme viewpoint, which should be informed by data from well designed studies.
ART clearly increases life expectancy for all groups, and this may be normalised in people without late diagnosis, complicated HIV histories, comorbidities or injecting drug use, especially if CD4 count return to >500 on treatment. Whether any additional health benefit is derived for people starting treatment at much higher CD4 counts is only likely to be adequately answered by START and its critical substudies. 
The largest impact on population mortality is more likely to come from reducing modifiable risk factors including earlier diagnosis and access to care and reducing risks associated with IDU.
Unless stated otherwise, references are to the Programme and Abstracts of the 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012, published as a supplement to Journal of the International AIDS Society 2012, 15 (Suppl 4).
- Saag M. When to start: as soon as possible. 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012. Oral abstract O112.
- Lundgren J. When to start: not so fast. 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012.Oral abstract O113.
- High KP et al. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. JAIDS: 1 July 2012, Volume 60 – Supplement 1.
- Justice A et al. Aging with HIV: one size does not fit all. 19th Conference on Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. Oral abstract 175.
- Reiss P. HIV, co-morbidity and ageing. 11th Intl Congress, Glasgow, 2012. Oral abstract O121.
- Shiels MS et al. Age at Cancer Diagnosis among persons with AIDS in the US. Ann Intern Med 2010:153:452-460.
- Schouten J et al. Comorbidity and ageing in HIV-1 infection: the AGEhIV Cohort Study. 19th IAS Conference, Washington, 2012. Abstract THAB0205.
- Sabin C. Review of life expectancy in people with HIV in settings with optimal ART access: what we know and what we don’t. 11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012. Oral abstract O131.
- Antiretroviral Therapy Cohort Collaboration (ART-CC). Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372:293–299.
- May M et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 2011;343: doi: 10.1136/bmj.d6016.
- Nakagawa F et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012; 26:335-43.
- Losina E. Racial and Sex Disparities in Life Expectancy Losses among HIV-Infected Persons in the United States: Impact of Risk Behavior, Late Initiation, and Early Discontinuation of Antiretroviral Therapy. Clin Infect Dis 2009; 49:1570-8.
- Lewden C. All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Int J Epidemiol 2012; 41:433-45. April 2012. Epub 28 Nov 2011.
- Strategic Timing of AntiRetroviral Treatment (START) study.