Information for patients
Research is essential if we are to understand more about HIV infection and to get better and safer treatments. The research carried out by ART-CC is focussed on patients who are receiving antiretroviral therapy. Several ART-CC papers have contributed to treatment guideline development.
Research includes papers on:
- Comparing treatment response in South Africa, North America and Europe
- Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV patients
- Deaths in patients with HIV that are virally suppressed for more than 3 years but do not completely recover their CD4
- How does gender affect treatment outcomes?
- Normal life expectancy with CD4 count above 200 and low viral load after 1 year of ART
- The VACS Index: an internationally generalizable risk index for mortality after one year of antiretroviral therapy
- Higher rates of AIDS during the first year of antiretroviral therapy among migrants: the importance of tuberculosis
- How often do patients switch from their first ART regimen and which patients are most likely to do this?
- How does country of origin affect treatment outcomes?
- Do comparisons of drugs in trials agree with results from clinical cohorts?
- The effect of injection drug history on disease progression
- Non-AIDS deaths exceed AIDS deaths after four years of Antiretroviral Therapy
- When should HIV-positive people start treatment?
- Latest CD4 count of patients treated with ART for 3 years is best predictor of good outcomes
- Life expectancy of individuals treated with ART has increased by 13 years in era of combination antiretroviral drugs
- Prognosis taking into account response to ART
- How well people do from the time of starting treatment
Currently we are investigating the effects of:
- low-level viremia
- adherence to treatment
- HIV subtype
- long term treatment on ART
- CD4:CD8 ratio
- year of starting ART
on patient outcomes.
ART-CC is also actively looking at questions on switching (Office document, 77kB) to 2nd line therapy, for example:
- When should a patient switch drugs?
- How well do patients do after switching and does this vary by 2nd drug combination?
Further information for patients can be found on the HIV treatment information base.
After 2 years on HIV treatment, survival in South African patients is at least as good as those in North America. South Africans with HIV have similar chances of staying alive beyond 2 years on antiretroviral therapy (ART) as North Americans. This is when ART treatment is started promptly.
Rates of death were looked at in cohorts in South Africa, North America and Europe. Patients were studied for up to 4 years after starting ART.
We looked at the first year of treatment. We found patients in South Africa had higher rates of deaths than those in North America or Europe. This could be because the immune systems of South African patients had been damaged more from HIV. This is shown by lower CD4-cell counts at the start of treatment. The study then looked at those on ART between 2 and 4 years. Rates of death in North American patients were the same as or higher than those for South African patients.
There are differences between North America and South Africa that could affect survival on ART. Hepatitis C infection may cause more deaths between 2-4 years in the North American patients. In South Africa those getting care may have been very motivated patients. This was because they got care in the early years of the programs when treatment was harder to come by.
Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV patients
Patterns of why patients with HIV are dying have changed a lot after antiretroviral therapy (ART) was introduced.
We looked at 65,121 patients. Of these 6.5% died. The longer the patient was on ART, the less likely dying from AIDS became. Mortality from non-AIDS cancers increased though. During the first year of ART men were more likely to die than women. This was mostly due to non-AIDS cancers and liver-related deaths. Cardiovascular disease, heart/vascular and cancer deaths were strongly linked to age.
Patients with a history of injection drug were more likely to die from all types of death. This was particularly the case for liver-related causes. CD4 count was a very good predictor of AIDS, non-AIDS infection and non-AIDS cancer deaths for all patients. igh viral load was linked with deaths from AIDS and from non-AIDS infection.
We need better understanding of patterns of why HIV patients die from different causes of deaths. This can aid in development of good care for HIV-infected individuals and inform rules for dealing with risk factors.
Deaths in patients with HIV that are virally suppressed for more than 3 years but do not completely recover their CD4
Some HIV patients that start antiretroviral therapy (ART) with low CD4 counts achieve viral suppression. Some never reach normal levels of CD4 count. We wanted to work out:
- Risk factors for failure to achieve CD4 count greater than 200 cells after having viral suppression for 3 years.
- The link between the CD4 count and subsequent mortality.
We included patients that were suppressed for more than 3 years. They also had a CD4 count of less than 200 cells at the start of the time they were suppressed.
We found there were many risk factors for not achieving a CD4 count of greater than 200 cells. These were:
- Increasing age
- Lower CD4 count at ART start
- Heterosexual men (rather than women or men who have sex with men)
- A history of injection drug use
- Starting ART after 1998
- Longer time from start of ART to becoming virally suppressed
We compared mortality in two groups of patients that had been virally suppressed for 3 years. There were more deaths in the group who still had a CD4 count below 200 cells. There were less deaths in those who increased their CD4 count above 200 cells. This increase in deaths was seen for all types of patients and for all causes of death.
Virally suppressed HIV patients on ART who do not achieve a CD4 count greater than 200 cells have more chance of dying in the long-term.
It is well known that women are likely to live longer than men. However, death rates for HIV-positive men and women change with location. ART-CC looked at differences in how long men and women with HIV live across the US, Canada and Europe.
We found that in Europe, women with HIV were expected to live longer than men. In Canada and the US, there was no difference between the sexes. We also looked at deaths due to AIDS and deaths which were not due to AIDS. In Europe, women had similar rates of AIDS deaths compared to men. However, women had lower rates of non-AIDS deaths. In Canada and the US there were no differences in either AIDS or non-AIDS deaths.
There were fewer differences in death rates between the sexes in Canada and the US, compared with Europe. This is probably due to differences in factors like wealth and race of HIV-positive women in the three regions. In Europe, the HIV epidemic in women probably does not result in as much social exclusion as in Canada and the US. In Canada and the US HIV/AIDS impacts First Nations and African- American women more than other groups of women.
The differences in death rates for men and women in treated HIV positive people may become more like those in the non-HIV population. Men may have less access to care than women. This may mean that the trend of more deaths in HIV positive men than women will carry on.
HIV-positive 35-year-old men and women in the United Kingdom (Great Britain) can expect to live about as long as people in the general population, if they have a CD4 count above 200 and a viral load below 400 copies after 1 year of antiretroviral therapy (ART). But people with a CD4 count below 200 when they start antiretroviral therapy have a lower expected age at death than people in the general population.
As HIV-positive people live longer thanks to antiretroviral therapy, studies show that they can expect to live about as long as people without HIV. Longer life with HIV depends on gaining CD4 cells and reaching an undetectable viral load. But previous studies have not looked closely as how many CD4 cells an HIV-positive person has to gain to live as long as an HIV-negative person the same age. Reaching an undetectable viral load is another signal of a good response to antiretroviral therapy. But the impact of viral load on life expectancy remains unclear.
To address the questions of how changes in CD4 count and viral load affect life expectancy, researchers in the United Kingdom (UK) conducted a large study of HIV-positive people in care between 2000 and 2012. The analysis focused 21,388 antiretroviral-treated people, 14,742 (69%) men and 6646 (31%) women. Two thirds of the men were white, while three quarters of the women were black African. Most men (73%) and most women (64%) were between 30 and 49 years old. Similar proportions of men and women started antiretroviral therapy in 2000-2002 (21% and 22%), 2003-2005 (26% and 30%), 2006-2008 (32% and 30%), and 2009-2010 (22% and 18%). Over the study period, 961 people (4.5%) died. Overall mortality was higher in men than women (9.0 versus 7.9 per 1000 person-years). But among people younger than 45, men and women had the same mortality (7.9 per 1000 person-years, meaning about 8 of every 1000 people died every year).
This large study of HIV-positive people in care in the United Kingdom (Great Britain) found that women and men who have a CD4 count above 200 and a viral load below 400 copies after 1 year of antiretroviral therapy can expect to live as long as women and men in the general population. But people who start antiretroviral therapy after their CD4 count falls below 200—and people who fail to reach a CD4 count above 200 after 1 or more years of therapy—have an earlier expected age at death than people in the general population of the UK. All of these findings apply only to people infected with HIV during sex—not to people infected while injecting drugs or infected around the time of birth. These encouraging findings about life expectancy in people who respond well to antiretroviral therapy reflect results of other recent studies in the United States and Canada, two international antiretroviral trials, the Netherlands, and France. Together these studies show that, in general, HIV-positive people who reach an undetectable viral load and gain CD4 cells with antiretroviral therapy can expect to live about as long as people the same age and gender in the general population.
The VACS Index: an internationally generalizable risk index for mortality after one year of antiretroviral therapy
Antiretroviral therapy (ART) has so far worked very well. However there are still extra deaths in patients with HIV. We wanted to develop a practical risk score for patients with HIV taking ART.
As well as age, the VACS Index is based on both markers of HIV disease (CD4 cell count, viral load) and markers of organ damage (haemoglobin, aspartate and alanine transaminase, platelets, creatinine and hepatitis C status). We compared this with a Restricted Index based only on age, CD4 cell count and viral load. We looked at deaths up to 6 years after starting ART.
The VACS Index was better able to predict if patients would die. This was both for HIV deaths and non-HIV deaths. It was more accurate for both younger and older men and women. It also worked for those with and without a very low viral load, and for those with and without hepatitis. The VACS Index may prove a useful tool for doctors and patients.
Higher rates of AIDS during the first year of antiretroviral therapy among migrants: the importance of tuberculosis
In lower-income countries rates of AIDS-defining events (ADEs) and death are high during the first year of antiretroviral therapy (ART). We looked at differences between foreign-born (migrant) and native-born (non-migrant) patients starting ART in Europe, the US and Canada. We examined rates of the most common ADEs and mortality during the first year of ART.
Of 48, 854 patients, 25.6% were migrants:
- 16.1% from sub-Saharan Africa,
- 5.6% Latin America,
- 2.3% North Africa/Middle East,
- 1.6% Asia.
There was a similar amount of ADEs for migrants and non-migrants during the first year of ART. Rates of tuberculosis were higher in migrants than non-migrants though. There were more deaths among non-migrants than migrants although some of this was partially explained by patient characteristics at start of ART.
During the first year of ART, HIV-positive migrants had higher rates of ADEs than non-migrants. Tuberculosis was the most common ADE among migrants. This highlights the importance of screening for tuberculosis prior to starting ART in these patients.
People with HIV have traditionally struggled to get life insurance. Many are routinely turned down. Since 1996 there have been many improvements to HIV treatment, including new regimens and one pill per day formulations. These changes have led to much improved outcomes for people with HIV. In this study we looked at the excess mortality in successfully treated people with HIV. We have shown that for certain low-risk groups, the extra mortality risk is low. This means that life insurance up to 20 year terms could be offered at affordable premiums to low-risk people with HIV. This would have many benefits, for example mortgage cover.
How often do patients switch from their first ART regimen and which patients are most likely to do this?
The choice of first ART regimen is important. These regimens must be able to quickly reduce the amount of HIV virus, have few side effects, and be as simple to take as possible. Patients sometimes need to make a change to the first regimen. This could be because of treatment failure or because of bad side effects. This study looked at when and why HIV patients changed or interrupted their first ART regimen.
For the purposes of this study a change of regimen meant: a change of drug class, changing drugs within drug classes or a switch to a nonstandard regimen. An interruption of regimen was stopping all ARV drugs for at least 1 month.
At three years after ART start, 47% of patients had changed first ART regimen. 12% of patients interrupted and 2% had died without making any regimen change.
- Rates of interruption were highest for those that got HIV through injection drug use. They were lowest for men who have sex with men. They were higher for patients starting ART with a CD4 cell count above 350 cells/μl, than for other patients.
- Patients on lopinavir and other protease inhibitors changed from their first regimen more often than patients on efavirenz. They also interrupted their first regimen more often.
- Patients on atazanavir changed class less than those on efavirenz.
- Patients on nevirapine had higher rates of interruption than those on efavirenz.
- Those on tenofovir/emtricitabine had the lowest rates of substitutions and switches to nonstandard regimen.
- Those on abacavir/lamivudine had the lowest rates of interruption.
- Rates of substitution and switches to nonstandard regimen were lower in 2006-2009 than 2002-2005.
Rates of changing drugs and interruption were high. They were very high in patients in their first year of ART. There have been less substitutions and switches to nonstandard regimen in recent years. This may be linked to more use of once-daily drugs that are easy to take.
Rates of death for HIV-positive people may differ according to their place of birth, ethnic group or race. We looked at whether this was the case across the US, Canada and Europe. We did this by looking at data on the country of origin, ethnic group or race. The patients we examined were taking antiretroviral therapy (ART).
We found that migrants died less often. This suggests a so-called “healthy migrant” effect. This is where only those fit and able to work would migrate to another country. However, there was higher rate of deaths among First Nations people and African Americans in North America. This suggests social inequality gaps.
Clinical trials are used to compare antiretroviral (ART) drugs. They are used to provide evidence for guidelines and treatment decisions. We do not know whether the results found in the trials are the same as we see in the general patient population treated through routine care. They might differ because of how patients are chosen for clinical trials. Patients that volunteer for trials may differ from those who do not want to take part. We took the results from two trials carried out by the Adult AIDS Clinical Trial Group (ACTG 5095 and 5142). We compared these two trials with results from patients observed in routine care (ART-CC).
The trials compared ART regimens containing several drugs. These were either efavirenz (EFV), Lopinavir boosted with ritonavir (LPV/r) or Abacavir (ABC). The trials were looking for how much viral load the patients had at 24 and 48 weeks after starting treatment. The routine care results from ART-CC were close to those from the ACTG trials. This means that ART drug performance in clinical trials is similar to in routine care settings.
HIV-positive patients infected through injecting drug use (IDU) have a higher chance of death than those infected through sex. We wanted to work out the reasons for this. The study looked at patients from the start of treatment with antiretroviral therapy (ART). We wanted to see if IDU patients died at the same rate as non-IDU patients. We also wanted to look at whether the causes of death were different for the two groups.
We found that at start of ART, lower CD4 cell count, higher HIV viral load and an AIDS diagnosis was linked to a higher chance of death in both IDU and non-IDU. More of the IDU group than the non-IDU group started ART with a low CD4 cell count and fewer had been diagnosed with AIDS. Despite this, the rates of death in the IDU group were twice those in the non-IDU group.
IDU patients had higher rates for all the causes of death. We found that CD4 cell count predicted death better for non-IDUs than in IDUs. This means that more deaths in the IDU group were linked to factors not related to HIV. Liver-related deaths and deaths from direct effects of substance abuse appear to explain many of the deaths in IDUs. However, they are also at a higher risk for many other causes of death. This may be because of worse management of HIV disease in these patients. A problem with our study was that we did not have data on whether the patients in the IDU group were still abusing substances. More research is needed on the role of hepatitis C infection, which is a major cause of liver disease. To explain the worse outcomes of IDU patients we need more research on ongoing substance abuse and whether patients are taking their ART drugs when they are meant to (adherence).
Our research shows that although ART continues to dramatically reduce rates of mortality from HIV infection in high-income countries, those infected with HIV have high mortality from causes of death other than AIDS, particularly cancers and liver disease.
The study involved nearly 40,000 patients who started ART between 1996 and 2006 in Europe and North America. Of the 1,876 deaths that occurred in that time, a definitive cause of death could be assigned to 85% of cases. Overall, almost 50% of patients died from AIDS which remains the most common cause of death.
However, although during the first year of treatment with ART the majority of deaths were AIDS-related, because rates of AIDS death decline with time on ART, non-AIDS deaths exceeded AIDS deaths after approximately 4 years of ART.
Lifestyle-related causes of death such as suicide, drug overdose and liver diseases (mainly due to hepatitis) were the most frequent causes (15%) of non-AIDS deaths, and the most common non-AIDS cancer reported was lung cancer (37% of all non-AIDS cancer deaths, 4% of deaths) which was probably associated with smoking.
Increases in rates of deaths from causes associated with aging, such as other cancers (12%) and cardiovascular disease (6.5%), imply that the process of aging will become a dominant factor in HIV mortality in the next decade.
Rates of AIDS deaths were lower after the year 2000 which may be due to newer ART drugs having better potency and tolerability.
We also found a strong inverse association of rates of AIDS death with CD4 counts at the time of starting ART, which supports arguments for earlier initiation of ART.
Interventions to address risk factors for lifestyle-related causes of death such as those described above, as well as monitoring for and care of diseases associated with old age will be necessary if the full benefit of ART in decreasing mortality is to continue in the second decade of ART.
We studied more than 45,000 people with HIV in Europe and North America. Our study suggests that starting ART with a CD4 count of 351-450 means less chance of AIDS and death than waiting until CD4 count is 251-350.
The CD4 count at which ART should be started is a big issue in the care of HIV-positive people. At the time of this study, there were no randomised controlled trials that had looked at this issue, so this was the first study of its kind. However, a trial is now being done looking at this issue. It is called the “START” trial.
HIV patients in our study started ART on or after January 1st 1998 and were followed up from the start of treatment. These patients did not have AIDS, had a CD4-cell count less than 550 cells per µL and had no history of injecting-drug use.
Those that waited to start ART when they had a CD4 count of 251-350 had a 28% higher rate of AIDS and death than those who started ART in the range 351-450. Waiting to start ART in the above ranges was also linked to a 13% higher rate of death).
When thinking about when to start ART, there are other issues to take into account as well the chance of AIDS and death. At the moment there is no cure for HIV. This means that HIV patients are expected to take ART treatment for their entire life. ART drugs can be inconvenient to take, and may have side-effects. However, these effects can mostly be avoided through careful choice of ART drug regimen.
We found evidence that waiting to start ART treatment until the patient's CD4-cell count is less than 350 was linked to increased rates of AIDS and death. There are now fewer concerns about side-effects. Due to this our results suggest that 350 should be the minimum threshold at which ART should be started.Unfortunately, many patients are not diagnosed with HIV until their CD4 count has fallen well below 350, sometimes even below 200. It is important that people at possible risk of having HIV get tested regularly so that if found to be infected, they can receive care and treatment.
The CD4 count and viral load are well known to predict AIDS and death in people with HIV. In patients on ART for at least 3 years we looked at the importance of these values measured at ART start, and at 6 and 36 months later.
Over 14,000 adult patients from 15 HIV cohorts were included in this study. They were all followed for at least 36 months after start of ART. The median CD4 counts at 0, 6 and 36 months were 210, 320 and 450 respectively. 78% of patients achieved a viral load below 500 copies/mL at 6 months. CD4 count at 36 months was the strongest predictor of AIDS and death. We found that although current values of CD4 cell count and viral load are the most important factors for subsequent AIDS and death rates in HIV-positive people treated with ART, changes in CD4 from 6 to 36 months and the value of 6-month viral load are also prognostic for AIDS, but not measures taken at start of ART.
Life expectancy of individuals treated with ART has increased by 13 years in era of combination antiretroviral drugs
Since ART was introduced in 1996, regimens have become more effective, better tolerated, and have been simplified in terms of dosing. However, the effect of HIV on life expectancy in the era of combination therapy is not well understood.
This collaboration of 14 cohorts in Europe and North America analysed 18587, 13914, and 10584 patients who started ART in 1996-99, 2000-02, and 2003-05 respectively. 2056 patients died during the study period, and mortality decreased from 16.3 deaths per 1000 person-years to in 1996-99 to 10.0 in 2003-05. This was a drop of 39%. Potential life years lost per 1000 person-years also decreased over the same time, from 366 to 189 — a fall of 48%. Life expectancy increased from 36.1 years in 1996-99 to 49.4 years in 2003-05, an increase of more than 13 years. Patients treated later in the course of their infection, with lower CD4 cell counts (below 100 cells per μl blood), had lower life expectancy, at 32.4 years, compared with 50.4 years in patients with treated earlier with higher CD4 counts (above 200 cells per μl). Patients with presumed transmission via injecting drug use had a lower life expectancy (32.6 years) than those from other transmission groups (44.7 years). Finally, women had a slightly higher life expectancy than men (44.2 v 42.8 years), which may be due to women on average starting treatment earlier.
Despite these positive results, an HIV-positive person starting cART at age 20 will only, on average, live another 43 years (to age 63). This is compared to a 20- year-old HIV-negative person in a high-income country who can expect to live to around 80 years. This last finding leads the authors to call on health planners to improve health services and living conditions for HIV-infected patients to reduce this gap.
The reductions in mortality and gains in life expectancy over the three periods studied here are probably the result of both improvements in ART and continuing declines in mortality rates among patients on treatment for long periods. These advances have transformed HIV from being a fatal disease into a long-term chronic condition.
In summary, this study shows that people living with HIV in high-income countries can expect increasing positive health outcomes on ART. The marked increase in life expectancy since 1996 is a testament to the gradual improvement and overall success of treatment.
We then looked at response to ART in the first 6 months. We found that viral load and CD4 count measured at 6 months strongly predicted survival after 6 months. The values measured at start of treatment were no longer important to predict survival. In other words, it matters what CD4 count and viral load a person arrives at, but not where the person was when starting ART. This should be seen as a positive message, which should motivate people to adhere to treatment.
Our first paper on prognosis was published in 2002. It included data on over 12,000 adults from Europe and North America. Patients started treatment in 1995-2001 on at least 3 ART drugs. They were followed from the start of treatment to see if they got AIDS defining diseases or died.
CD4 cell count at the start of ART strongly predicted outcomes. Other predictors of poorer outcomes were: higher viral load, older age, infection via injection drug use, and having an AIDS disease before starting ART.
The most common AIDS diseases were:
- candidiasis in the throat,
- Kaposi’s sarcoma,
- Mycobacterium Avium disease,
- non-Hodgkin lymphoma and
- pneumonia (PCP).
The probability of death within 3 years of starting ART ranged from 0.8% to 43%. It was lowest for those under 50 years old with no AIDS diagnosis and no history of injection drug use who started ART with CD4 count above 350 and viral load below 10000 copies/mL. It was highest for those over 50 years old, with AIDS and a history of injection drug use who started ART with CD4 count below 50 and high viral load.