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Antiretroviral failure rate falls from over 60% to under 10% in France.

Rates of virologic failure (a detectable viral load * during antiretroviral therapy) fell from over 60% in 1997-1998 to under 10% in 2009-2011 in France. (1) Compared with starting therapy in 1997-1998, starting in 2003-2004 almost halved chances of failure, and starting in 2007-2009 lowered chances of failure almost 80%.

Around 1996 antiretroviral therapy improved dramatically as HIV providers began combining three drugs from two antiretroviral classes. Treatment with three antiretrovirals has remained the standard approach since then, but new classes of antiretrovirals have become available and new antiretrovirals in each class have become safer and easier to take.

Because of these improvements, antiretroviral therapy today lowers viral loads to an undetectable level more consistently, and more people can continue the same regimen without interruption. Trials of. new antiretrovirals and new strategies show that high proportions of trial participants now regularly reach an undetectable viral load. But these trials usually last only 1 or 2 years, and the trials often exclude people with advanced HIV infection or other illnesses like liver or kidney disease. As a result, antiretroviral success rates in these trials may not reflect what happens in the month-to-month care of everyone who starts treatment.

To get a better understanding of how response to antiretroviral therapy has changed over the years in treated people across an entire country, researchers in France conducted this study. The researchers also aimed to identify factors linked to success or failure of antiretroviral therapy over the years.

France is similar to the United States in antiretroviral combinations and strategies and in the general care of HIV-positive people. A key difference between the countries is that antiretroviral therapy and HIV care are free in France.

* How the study worked. This analysis involved HIV-positive people in the French Hospital Database on HIV, an ongoing study that includes patients seen in HIV clinics at 70 hospitals across France. Researchers collect medical information on these patients at least every 6 months or any time their health changes or they begin a new treatment. Research shows that people in the French Hospital Database on HIV reflect the entire HIV population in France.

People could be included in the new analysis if they received care between 1997 and 2011 and if they took antiretrovirals for at least 6 months. The researchers defined virologic failure in two ways:

* Two consecutive viral loads above 500 copies more than 6 months after treatment began

* One viral load above 500 copies more than 6 months after treatment began, followed by a switch in antiretrovirals

The researchers counted how many people had a virologic failure in 1997-1998, 1999-2000, 2001-2002, 20032004, 2005-2006, 2007-2008, and 2009-2011. They did not include virologic failures that followed interruption of antiretroviral therapy.

Next the researchers used a standard statistical method to see how the failure rate changed from 1997-1998 to each later period. This type of analysis considers the impact of several factors that may influence virologic failure, such as age, gender, mode of HIV transmission, hepatitis C virus infection, and type of antiretroviral therapy when treatment began. Thus the researchers can pinpoint individual factors that affect chances of virologic failure regardless of whatever other risk factors a person has.

* What the study found. The study involved 81,738 people with HIV who had a median number of 11 viral load measures through a median of 9.4 years. While 33% of study participants were gay or bisexual men, 18% were heterosexual men, 24% were heterosexual women, and 15% acquired HIV when injecting drugs. Across the study periods, 14% of the group came from sub-Saharan African countries. Slightly more than one quarter of the study population, 29%, had taken one or two antiretrovirals before starting a three-drug combination, which became the standard treatment around 1996.

Median age of the study group rose from 37.2 years in 1997-1998 to 46.6 years in 2009-2011. Over the same period, median CD4 count at the time of virologic failure climbed from 340 to 530, while viral load at failure fell from 7032 copies to 2536 copies (Figure 1).

The proportion of people with at least one virologic failure in any 2-year period dropped steadily from 61.5% in 1997-1998 to 9.7% in 2009-2011 (Figure 2). In the same period, proportions of people with a viral load of 500 to 999 copies dropped from 11.2% to 2.7% and the median viral load at the time of virologic failure fell from 7032 copies to 2536 copies.

Statistical analysis accounting for several factors that can affect virologic failure determined that chances of failure fell by 26% from 1997-1998 to 1999-2000, by 36% to 2001-2002, by 46% to 2003-2004, by 62% to 2005-2006, and by 79% to 2007-2009. Compared with people who had a CD4 count below 200 at the time of virologic failure, those with a CD4 count of 200 to 349 had a 34% lower chance of failure, those with a CD4 count of 350 to 499 had a 54% lower chance of failure, and those with a CD4 count of 500 or more had a 72% lower chance of failure.

For the years 2006 through 2011, the researchers conducted a separate analysis defining virologic failure beyond 6 months of treatment as (1) two consecutive viral loads above 50 copies or (2) one viral load above 50 copies followed by a switch in antiretrovirals. Defined this way, the virologic failure rate fell from 22.1% in 2006 to 18.5% in 2007, 16% in 2008, 13.7% in 2009, 12.1% in 2010, and 10.1% in 2011. Over that period, median viral load at virologic failure dropped from 528 copies to 171 copies.

* What the results mean for you. This large and long study in France, where antiretroviral treatment practices and available antiretrovirals are similar to the United States, found that the proportion of people whose antiretroviral regimen failed fell steadily and consistently over the 15 years from 1997 to 2011. This continuing drop in the virologic failure rate confirms that antiretroviral therapy has been working better and better since three-drug combinations became standard around 1996. The findings reflect results from other countries where the same antiretrovirals have been available--Canada, (2) the United Kingdom, (3-4) and Switzerland. (5)

The French team also found that viral load at the time of virologic failure declined over the years. One reason for this change could be that in more recent years HIV clinicians stopped antiretroviral combinations faster and switched to a new combination when a treated person had a detectable viral load. That practice reflects French and US guidelines that recommend quick assessment of what caused the detectable viral load and a quick switch to new antiretrovirals if necessary. Continuing the same antiretroviral combination in a person who has a low but detectable viral load can make HIV resistant to drugs in the current combination and sometimes to other drugs--and resistant virus can be harder to treat.

Many factors could contribute to these improvements in virologic failure rates, including (1) availability of more antiretrovirals, (2) more antiretroviral classes that attack HIV in different ways, (3) stronger antiretrovirals, (4) antiretrovirals with fewer side effects, (5) antiretrovirals that are easier to take (because of once-daily dosing or combining two or more antiretrovirals in the same pill), (6) better pill-taking habits by people with HIV (often because of reasons 4 and 5), and (7) better understanding of how to treat HIV by providers.

A notable aspect of this study is that it included anyone taking antiretrovirals for 6 months or more, not just people starting their first antiretroviral combination. So the study group includes people in whom one or more antiretrovirals failed. Because no many new and different antiretrovirals became available in the 2000s, clinicians can often build a combination that will control HIV after one or more combinations have failed. An undetectable viral load should be the goal of treatment regardless of how many antiretrovirals have already failed.

The study also found that a higher current CD4 count lowered chances of virologic failure. That finding supports recent recommendations to start antiretroviral therapy before the CD4 count falls to a low level. Indeed, US guidelines say everyone with HIV should start antiretroviral therapy, no matter what their CD4 count. (6)

Taken together, these findings are good news for people with HIV. The results should inspire confidence that today's antiretroviral combinations and treatment strategies control HIV better than older combinations. To profit from these newer treatments, people with HIV should take their antiretrovirals regularly, exactly as instructed by their HIV providers.

References

(1.) Delaugerre C, Ghosn J, Lacombe JM, et al. Significant reduction in HIV virologic failure during a 15-year period in a setting with free healthcare access. Clin Infect Dis. 2015;60:463-472.

(2.) Cescon A, Kanters S, Brumme CJ, et al. Trends in plasma HIV-RNA suppression and antiretroviral resistance in British Columbia, 1997-2010. J Acquir Immune Defic Syndr. 2014;65:107-114.

(3.) Bansi L, Sabin C, Delpech V, et al. Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations. HIV Med. 2010;11:432-438.

(4.) Lampe FC, Smith CJ, Madge S, et al. Success of clinical care for human immunodeficiency virus infection according to demographic group among sexually infected patients in a routine clinic population, 1999 to 2004. Arch Intern Med. 2007;167:692-700.

(5.) Ledergerber B, Cavassini M, Battegay M, et al. Trends over time of virological and immunological characteristics in the Swiss HIV Cohort Study. HIV Med. 2011;12:279-288.

(6.) Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 13, 2014. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

* Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts.
Figure 1. In a nationwide French study of almost 82,000
people, median CD4 count at the time of virologic failure
rose steadily from 1997-1998 to 2009-2011. Over
the same period, median viral load at virologic failure
fell steadily.

CD4 count and viral load at
virologic failure in France

            CD4 count   Viral load

1997-1998     340        7032
2001-2002     430        5469
2005-2006     451        4269
2009-2011     530        2536

Note: Table made from line graph.

Figure 2. From 1997-1998 to 2009-2011, the proportion
of French people with virologic failure of their antiretroviral
combination fell from more than 60% to under
10%. Across the same span, proportions of people
with a viral load of 500 to 999 copies dropped.

Changing proportions of
virologic failures in France

            Under 500   500-999

1997-1998     11.2%      2.7%
2009-2011     61.5%      9.7%

Note: Table made from bar graph.
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Title Annotation:Article 3
Publication:HIV Treatment: ALERTS!
Geographic Code:4EUFR
Date:Apr 1, 2015
Words:1778
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