When taken every day exactly as directed, HIV therapy (ART) can eventually reduce the amount of HIV in the blood (viral load), usually to a level which cannot be detected with routinely used tests. This very low level of HIV is commonly called undetectable. Reaching and maintaining an undetectable viral load leads to improved health and an increased likelihood of near-normal life expectancy. Furthermore, clinical trials have found that if people with HIV continue to take ART every day to maintain an undetectable viral load, they do not pass on HIV to their sexual partners.
These twin benefits of ART -- improved health and prevention of HIV transmission -- have led the Joint United Nations Programme on AIDS (UNAIDS) to encourage cities, regions and countries to reach the following goals by the year 2020:
- 90% of people who have HIV will be aware of their infection status
- 90% of people diagnosed with HIV will receive ART
- 90% of people taking ART will have an undetectable viral load
The path from HIV testing to diagnosis to care to treatment is called the HIV care cascade or the cascade of HIV care; some researchers refer to it simply as the Cascade. At every step of the cascade there is a potential for delays and for people to fall out of care. Plugging holes in the cascade is essential to helping HIV-positive people achieve timely care and good health, and, ultimately, for health authorities to reach their 90-90-90 targets.
In British Columbia
Researchers at the B.C. Centre for Excellence in HIV/AIDS have been collecting health-related information from HIV-positive people in studies for many years. From time to time this information is analysed and reports are produced.
In their latest analysis, a team of B.C. researchers assessed health-related information collected over many years from more than 8,000 HIV-positive people to find out about trends in treatment interruption. The researchers found that over the course of the study nearly 40% of participants interrupted their first regimen at least once. About 50% of treatment interruptions occurred about a year after ART had been initiated. The good news is that the proportion of people who interrupted therapy decreased significantly over the span of the study. Not surprisingly, the researchers found that some people who interrupted ART had an increased risk of death.
The B.C. study underscores the importance of monitoring the cascade of care and developing ways to help patients re-engage with their care and treatment.
Researchers collected health-related information from 8,110 people who initiated ART between 1996 and 2015.
Researchers defined a treatment interruption as follows:
"... a minimum 90-day gap between the prescription refill date and the date when previously dispensed medications were expected to be [finished]."
The researchers chose a 90-day period based on the preliminary results of another ongoing study, also in B.C.
Among the participants who interrupted ART, researchers only focused on those whose CD4+ counts were available before, during and after the interruption. This point will be discussed later in this CATIE News bulletin.
The average profile of participants upon entering the study was as follows:
- age -- 41 years
- 81% men, 19% women
- major ethno-racial groups: White -- 60%; Indigenous -- 20%
- 37% of participants had a CD4+ count less than 200 cells/mm3
- 37% of participants had been exposed to hepatitis C virus (HCV)
- 33% of participants had a history of injecting street drugs
- 9% of participants had HIV with some degree of resistance to ART
The proportion of participants who interrupted their regimen decreased over time, as the following figures show:
- 1996 to 2003 -- 32%
- 2004 to 2007 -- 18%
- 2008 to 2011 -- 14%
- 2012 to 2014 -- 11%
Most interruptions occurred about 12 months after ART had been initiated.
Revisiting the SMART Study
The trend toward decreased likelihood of interrupting ART is good. In 2006, researchers who conducted a large well-designed study called SMART found that interrupting ART was linked to an increased risk of infections and death. Subsequently, HIV treatment guidelines strongly discouraged interrupting ART. It is therefore possible that the dissemination of the results of SMART may have been one substantial factor underpinning the decrease in interrupted therapy. Another possibility, as suggested by other studies, is that regimens commonly used for initiating ART in B.C. (and likely in the rest of Canada and other high-income countries) in the recent era are better tolerated.
Interruption and Survival
Based on deaths that occurred during the study, the researchers estimated the risk of death in the year following the interruption of ART and found that this risk was affected by a person's CD4+ cell count at the time of treatment cessation, as follows:
- a CD4+ count of 500 or more cells/mm3 was associated with a 2% increased risk of death
- a CD4+ count between 200 and 499 cells/mm3 was associated with a 4% increased risk of death
- a CD4+ count less than 200 cells/mm3 was associated with a 19% increased risk of death
Furthermore, taking many factors into account, the researchers found that the following factors were statistically linked to an increased risk of death once therapy was interrupted:
- older age
- having had a high viral load in the past
- having changed regimens multiple times
Bear in Mind
The findings from the B.C. study suggest that interruptions of ART are decreasing but still occur. The reasons that people interrupted therapy are not clear, as the present study was not designed to explore that issue.
However, the researchers suggested two reasons why people may have stopped taking ART, as follows:
- to avoid medication side effects
- they were suspicious of ART's effectiveness
It is clear from the B.C. study that more research needs to be done in at least the following two areas that can lead to interventions:
- finding ways to prevent treatment interruptions
- helping people who have interrupted ART re-engage with their care and treatment
The present study was imperfect -- it was not able to report on what happened to people who stopped taking ART and who also stopped making appointments to visit their clinic and local lab to have their CD4+ counts and viral load measured. Some of the people who did this may have moved to another province. But it is also possible, likely even, that some participants who stopped taking ART and who dropped out of care died. Such people (and any subsequent deaths) were not monitored by the study, as it only focused on those who maintained connections with clinics.
The B.C. study found important trends that require further investigation, not just in B.C. but in the rest of Canada as well. Research needs to be done, perhaps at the level of individual clinics, to find out why people stop taking ART. Without such research, doctors, nurses, pharmacists, peer navigators and case managers will remain at a loss when it comes to developing effective ways to prevent treatment interruptions and re-engaging patients into care. Such efforts are necessary if B.C. and the rest of Canada are to achieve and maintain the UNAIDS 90-90-90 targets by 2020.
CATIE statement on the use of antiretroviral treatment (ART) to maintain an undetectable viral load as a highly effective strategy to prevent the sexual transmission of HIV
Canada's progress towards global HIV testing, care and treatment goals -- CATIE News
Going beyond current ideas about the cascade of HIV care -- CATIE News
90-90-90 -- An ambitious treatment target to help end the AIDS epidemic -- UNAIDS
Progress on Ontario's HIV care cascade -- CATIE News
Alberta -- Reducing deaths by strengthening the HIV Treatment Cascade -- CATIE News
Gaps in British Columbia's HIV treatment cascade -- CATIE News
The HIV treatment cascade -- patching the leaks to improve HIV prevention -- Prevention in Focus
The Engagement Cascade -- The Positive Side
- Wang L, Min JE, Zang X, et al. Characterizing HIV antiretroviral therapy interruptions and resulting disease progression using population-level data in British Columbia: 1996 to 2015. Clinical Infectious Diseases. 2017; in press.
- INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. New England Journal of Medicine. 2015 Aug 27;373(9):795-807.
- Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. New England Journal of Medicine. 2016; 375:830-9. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1600693
- Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. Journal of the American Medical Association. 2016;316(2):171-81. Available from: http://jama.jamanetwork.com/article.aspx?articleid=2533066
- Gillis J, Loutfy M, Bayoumi AM, et al. A multi-state model examining patterns of transitioning among states of engagement in care in HIV-positive individuals initiating combination antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes. 2016 Dec 15;73(5):531-539.
- Supervie V, Marty L, Lacombe JM, et al. Looking beyond the cascade of HIV care to end the AIDS epidemic: Estimation of the time interval from HIV infection to viral suppression. Journal of Acquired Immune Deficiency Syndromes. 2016 Nov 1;73(3):348-355.
- Gisslén M, Svedhem V, Lindborg L, et al. Sweden, the first country to achieve the Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO) 90-90-90 continuum of HIV care targets. HIV Medicine. 2017 Apr;18(4):305-307.
- Colasanti J, Kelly J, Pennisi E, et al. Continuous retention and viral suppression provide further insights into the HIV care continuum compared to the cross-sectional HIV care cascade. Clinical Infectious Diseases. 2016 Mar 1;62(5):648-54.
- Krentz HB, MacDonald J, John Gill M. High mortality among human immunodeficiency virus (HIV)-infected individuals before accessing or linking to HIV care: A missing outcome in the cascade of care? Open Forum Infectious Diseases. 2014 May 7;1(1):ofu011.
- Lourenço L, Colley G, Nosyk B, et al. High levels of heterogeneity in the HIV cascade of care across different population subgroups in British Columbia, Canada. PLoS One. 2014 Dec 26;9(12):e115277.
- Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. New England Journal of Medicine. 2006 Nov 30;355(22):2283-96.