Smoking and life expectancy in people with HIV

A study published in January in the journal AIDS bolstered the view that HIV-positive people in developed countries who smoke lose more life-years to smoking than they do to HIV. The findings suggest that smoking is worse for an HIV-positive person’s life expectancy than is appropriately-treated HIV.

The researchers tracked a total of 17 995 HIV-positive people in European and North American cohorts for a total of 79 760 person-years. They calculated that among 35-year-old HIV-infected men, the loss of life-years associated with smoking was 7.9 years, while for HIV it was 5.9 (with narrow confidence intervals in both cases).

“Well-treated HIV-infected individuals may lose more life-years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritised,” the study concluded.

No similar studies have been done to establish whether smoking has the same impact on the life expectancy of HIV-positive people in developing countries. It is possible that factors such as delayed treatment initiation and the high prevalence of diseases such as tuberculosis (TB) might make the effect of smoking on life expectancy less pronounced.

Further research in this area must be a high priority for the AIDS response in South Africa.

 

Big changes to WHO essential medicines list

In May, the WHO published its updated Model List of Essential Medicines (EML). The EML is considered an authoritative source on which medicines countries should put on their national essential medicines lists. It is updated every two years.

The new WHO EML contains a number of high-priced medicines that are still under patent – a move which sends a clear message that countries need to find ways of reducing the prices of these medicines and making them available to people who need them. “When new, effective medicines emerge to safely treat serious and widespread diseases, it is vital to ensure that everyone who needs them can obtain them,” said WHO Director General Dr Margaret Chan in a WHO press release.  “Placing them on the WHO Essential Medicines List is a first step in that direction.”

Of particular relevance to South Africa was the addition of the medicines bedaquiline, delamanid and linezolid for the treatment of multi-drug-resistant tuberculosis (MDR-TB). The committee did however provide the usual qualification with these medicines, stating that “the Committee supports the use of these medicines recommended  in WHO guidelines, with careful selection of patients, close monitoring to control adverse events, and active pharmacovigilance.”

The most notable addition to the EML in relation to antiretrovirals for the treatment of HIV was the addition of the protease inhibitor darunavir.

The list also contains a number of new cancer medicines (trastuzumab, imatinib, and rituximab) and some of the recent breakthrough treatments for hepatitis C. The addition of the controversially priced, directly-acting antiviral hepatitis C medicine sofosbuvir (made by the pharmaceutical company Gilead) is particularly important. Currently this medicine sells for US$84 000 for a 12-week treatment course in the United States. Lower prices are available in other countries, but it remains unclear when this medicine will become available to the millions of people who need it across the globe.

Entecavir and tenofovir were added to the list for the treatment of hepatitis B. Access to entecavir remains limited in South Africa due to the high price of the medicine here. While the original patent on entecavir expired in 2011, the pharmaceutical company Bristol-Myers Squibb holds a number of secondary patents that prevent the importation of low-cost generic versions of entecavir from India.

 

LATE BREAKER

Start HIV treatment sooner, study shows

It’s important to start treating people with HIV sooner rather than later, according to the findings of a large clinical study which could change treatment in many countries – including South Africa.

The findings of the Strategic Timing of Antiretroviral Treatment (START) study are of huge importance to public health.

Currently, in South Africa and many other countries, people with HIV have a regular test called a CD4 count. CD4 cells are a vital component of the immune system fight against infection. When the CD4 counts of people with HIV drop to below 350 (cells per cubic millimetre), they are offered antiretroviral treatment (adults with HIV are also offered treatment if they are pregnant or get an AIDS illness or tuberculosis, irrespective of their CD4 count). It has been known for several years that waiting for the CD4 count to drop much lower than 350, say to 250, puts people at greater risk of AIDS or death.

Recently, following a change in World Health Organisation guidelines, South African Minister of Health Aaron Motsoaledi ruled that treatment should be triggered at a CD4 count of 500. But until now there has been no definitive answer to the question of when to start treatment, at least from the perspective of patient health. There is however clear evidence that people on antiretrovirals (and whose HIV has been suppressed in their blood) are unlikely to transmit HIV.

Nearly 4 700 adults with HIV from 35 countries are participating in START. All started the trial with CD4 counts above 500. About half the participants were randomly selected to start antiretrovirals immediately, and the rest deferred treatment until their CD4 counts reached 350. All patients know which part of the trial they are on, and participation is, of course, voluntary.

START was conceived in 2006. It began enrolling people in April 2009 and will end in December 2016. It was only expected to produce results by early 2017. However, a few days ago, the trial’s oversight board (known as the Data Safety Monitoring Board, or DSMB) examined the trial data, as they do regularly, and discovered that there were fewer cases of AIDS or death among patients who started treatment earlier. The difference was statistically significant, which means it is very unlikely to be due to chance. In fact there were 14 cases of AIDS or death among patients who were treated at once, versus 46 among those who started treatment later. Everyone in the START study who has not yet started antiretrovirals will be offered them now.

The study will continue because it aims to answer several other questions dealing with how HIV affects the kidneys, lungs, bones, liver, heart and brain.

The main sponsor of the trial is the United States National Institutes of Health (NIH). One in five patients on the trial is in Africa, with the Desmond Tutu HIV Centre in Cape Town having the largest number of participants of any site worldwide. A third of the participants are in Europe and a quarter in South America and Mexico. There are also participants in the US, Asia and Australia. (Source: HIV I-Base)

The trial’s principal investigator, Professor Jim Neaton of the University of Minnesota in the United States, is quoted on the NIH statement announcing the trial results saying, “The definitive findings from a randomised trial like START are likely to influence how care is delivered to millions of HIV-positive individuals around the world.”

Professor Francois Venter, former president of the Southern African HIV Clinicians Society, who is also on the START DSMB, described the results as “amazing” and “unexpected”.

There has been much debate in the HIV world about when to start treatment, and this trial settles the question. Yet there had been opposition to the START study from some HIV researchers and activists, who were not convinced it was necessary; which prompted Venter to say, “Thank goodness for good science.”

A leading AIDS activist involved in the trial, Simon Collins, wrote in response to the news that it was “unsettling that not everyone supported the study, when all we were really asking for was good evidence. It was even unsettling to see how passionately some people objected to START. The results show exactly why the study was needed. Nobody thought that early treatment would reduce AIDS events at very high CD4 counts. It is significant that most people who joined the study, stayed in the study. … So before going on to the many debates about the results, it is good to first pause for a moment to acknowledge the research team that drove this study, and the HIV-positive people, without which none of this would have been possible.”

In recent years, medical researchers, including Ben Goldacre, the author of the influential books Bad Science and Bad Pharma, have called for large clinical trials which answer straightforward questions of importance to public health. START is an example of such a trial.

Nathan Geffen, Groundup

 

What do the START results mean for HIV-positive people?

On 27 May 2015, at least 18 months earlier than anyone expected, one of the largest ongoing HIV studies announced early results.

The news was given at a high-level press conference in Washington by Dr Antony Fauci, head of the US National Institute for Allergy and Immune Diseases (NIAID).

Together with the surprise timing, the results themselves were also not what anyone had predicted.

The press release was right to say that the results will change HIV treatment guidelines across the world.

What is the study, and the key results?

This is an international study called Strategic Timing of AntiRetroviral Treatment (START).

Since 2009, it has been studying the impact of early treatment. This involved either starting when subjects’ CD4 count was still above 500, or waiting until it reached 350.

The excitement over the results is not just for doctors and researchers. The results are important for HIV positive people.

Main findings include:

• HIV treatment was safe for people starting HIV meds with a high CD4 count. Many people in START had a CD4 count above 800.
• Early treatment led to fewer serious AIDS-related illnesses, even at high CD4 counts.
• The biggest impact from early treatment was expected to be on illnesses such as heart, liver and kidney disease, and some non-AIDS cancers. The opposite was true. This is big news.
• The results were similar in in both low- and high-income countries. This should result in making HIV treatment more available in all countries.

Everyone in START will now have the chance to start early treatment, even at very high CD4 counts.

Why are the results so exciting?

The START results are important is for at least three related reasons.

Firstly, they will change the way HIV treatment is prescribed. For the last 30 years, most decisions to treat HIV have depended on the CD4 count dropping to a certain level. START should mean that the next step after an HIV diagnosis will now be treatment.

Secondly, the results show that the benefits of treatment and prevention overlap. Other studies have proven that treatment dramatically reduces HIV transmission. Now people using treatment as prevention (TasP) will know there are direct benefits for their own health, too.

Thirdly, this will make it easier to design programmes to end the AIDS epidemic.

Who was enrolled in START?

Any research study is really a story about real people, and the HIV-positive volunteers in START were interesting and diverse.

People were enrolled from 35 countries: from Europe, North and South America, Africa, Asia and Australia.

About half were gay men, and more than 1 in 4 were women. The average age was 36, but ranged from 18 to 81.

Everyone started with a CD4 count above 500, and the study followed people for an average of 3 years.

However, just as in the general population, people had other health issues.

• One third were current smokers.
• Half had one or more risks for heart disease.
• One in five had complications of high blood pressure.

The study included people with diabetes, hepatitis coinfection, people with alcohol and drug issues, and psychological problems including depression.

How much better was early treatment?

Because of the high CD4 counts, the risk of HIV illnesses was expected to be very low. This was shown in the overall results.

Less than 3% of people had serious complications. The number of these cases was lower than expected in both groups. However, the differences between the two groups were big enough to change the study. Early treatment will now be offered to everyone in the study.

People in the early treatment group had roughly half the risk of a serious HIV-related illness (reduced by 53%). The comparison with people starting later was very significant.

The early group had fewer cases of two HIV-related cancers – Kaposi’s Sarcoma (KS) and non-Hodgkin lymphoma (NHL), and fewer cases of tuberculosis (TB).

More details about these results are in the Q&A below.

Were there risks from earlier treatment?

Because only early results are released, we need to wait for details about specific risks.

We don’t know how many people became undetectable on treatment. We don’t have specific information about side effects. We don’t know whether drug resistance will be an important caution.

We also don’t know about how treatment affects overall quality of life.

As well as the main study, several sub-studies looked at these issues.

In general, though, the lower number of very serious illnesses is likely to mean that the benefits of early treatment still outweigh the risks.

What happens now?

The study will continue to follow everyone in the study.

• People who are already on treatment will continue with the same treatment and monitoring.
• People in START who are not yet on treatment will now be offered treatment.

Over the next two months, the researchers will collect outstanding information. This will go into a more detailed analysis.

These results are likely to be presented at the International AIDS Conference being held in Vancouver in July 2015. The results from the sub-studies will also be presented.

START has created a cohort of people that might have potential advantages for long-term follow-up that will never again be possible.

When the study eventually closes, there is a commitment to continue providing treatment for at least six months. This is so the health providers in each country take on this responsibility.

Community perspective

The START study was rooted in a community demand for good evidence.

When there is not good evidence, we have to rely on expert opinion. The lack of evidence often meant that guidelines in the past did not always get it right. The early years of HIV treatment included many examples of guideline changes after evidence became available.

The START study is therefore an important achievement for asking for evidence over opinion. Good evidence is an essential step towards getting good care. This might even be more important than the overall finding that supports use of ART at any CD4 count: it is the level of confidence that can be relied on when discussing the important question of when to start treatment.

With over 12 million people on HIV treatment globally, the decision for the best time to start treatment was too important not to want the best-quality evidence. This involved a randomised study. It also involved several thousand people volunteering to be part of the study.

A lot has happened since the first person enrolled. Early discussions about the study in 2009 included a worry that people might never agree to start at such high CD4 counts.

It was also unsettling that not everyone supported the study, when all we were really asking for was good evidence. It was even unsettling to see how passionately some people objected to START.

The results show exactly why the study was needed. Nobody thought that early treatment would reduce AIDS events at very high CD4 counts.

It is significant that most people who joined the study, stayed in the study. More people stayed connected to their care than is commonly reported even for a study of a new drug treatment.

So before going on to the many debates about the results, it is good to first pause for a moment to acknowledge the research team that drove this study, and the HIV positive people, without whom none of this would have been possible.

Simon Collins, HIV i-Base

Further information:

• i-Base Q&A on the START results:
• i-base.info/i-base-qa-on-the-start-study-results
• The press release and NIAID press release and NIAID Q&A are online:
• www.niaid.nih.gov/news/newsreleases/2015/Pages/START.aspx#
• The open DSMB reports are posted to the START website:
• insight.ccbr.umn.edu/start/index.php?study=start&page=&menu=about
• Technical report on the START study results in the i-Base HIV Treatment Bulletin:
• i-base.info/htb/28261
• Community web sites and newsletters are likely to cover this widely.