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Antiretroviral Treatment Breaks Limit CD4 Count Gains and Raise Death Risk

March 2011

An 8-year study of almost 2500 people in a Swiss HIV group found that people who interrupted antiretroviral therapy gained fewer CD4 cells and ran a higher risk of new AIDS diseases and death than people who took their antiretrovirals regularly.1

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The strong antiretroviral combinations available today help people avoid AIDS diseases and live longer, healthier lives with HIV. Compared with older antiretroviral combinations, newer triple-drug therapies have fewer side effects and are easier to take. Still, many people interrupt their antiretroviral treatment, sometimes without the knowledge of their HIV doctor.

Several trials compared structured antiretroviral breaks with steady therapy in people with HIV.2-4 In all these studies, people in the antiretroviral-interruption group stopped treatment if their CD4 count rose to a certain level, then restarted treatment if their CD4 count fell to a certain level. All studies found higher rates of new HIV diseases -- and sometimes non-HIV diseases -- in people who interrupted antiretroviral therapy than in those who never stopped taking their drugs.

Trials like these provide strong evidence that interrupting antiretroviral therapy has more risks than benefits. But these trials ran for only a few years. A large, ongoing HIV population study like the Swiss HIV Cohort Study can offer further insight into the impact of antiretroviral interruptions over a much longer period. With that goal in mind, researchers planned this analysis of the Swiss HIV Cohort Study.

  • How the study worked. The research team focused on 2491 members of the Swiss HIV Cohort Study who started at least a three-drug antiretroviral combination from January 1996 through July 2008. About two thirds of this group had never taken an antiretroviral before starting triple therapy. The researchers did not include people without a CD4 count or viral load measurement before starting therapy, and they did not include people who switched from three or more drugs to one or two. The investigators divided study participants into three groups:

    • Group A: 1271 people (51%) who interrupted triple therapy for at least 1 month.
    • Group B: 469 people (19%) who never interrupted triple therapy but had a viral load above 1000 copies at some point 6 months after starting triple therapy.
    • Group C: 751 people (30%) who never interrupted triple therapy and never had a viral load above 1000 copies 6 months after starting triple therapy.

    The Swiss researchers determined the proportion of people in each group who reached a CD4 count above 350 or above 500 during the study period. They also recorded rates of new AIDS diseases and death. Then the researchers used a standard statistical method to pinpoint predictors of failure to reach a CD4 count above 350 or 500. The factors they considered in this analysis were study group (A, B, or C), gender, age, duration of HIV infection, previous treatment with fewer than three antiretrovirals, intravenous drug use, hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, Centers for Disease Control and Prevention (CDC) stage C HIV disease (that is, an AIDS-defining disease), the year antiretroviral therapy began, and viral load, CD4 count, and CD8 count when starting triple therapy.

  • What the study found. The 2491 people studied had an average age of 38.1 years, and two thirds of them were men. Median CD4 count before triple therapy was higher in the group A than group B or C (249 versus 161 versus 199). A lower proportion of people in group A than in group B or C had an AIDS disease before starting triple therapy (18.9% versus 27.5% versus 20.8%), and a higher proportion in group A injected illegal drugs (28% versus 13% versus 14.2%). Group A also had a higher proportion of people infected with HCV (36.1% versus 25% versus 21%) and a somewhat higher proportion of women (35% versus 27.7% versus 29.8%).

    Observation time of study participants averaged 7.1 years. Half of the study group (51%) interrupted antiretroviral therapy at least once. For the whole study group, the median CD4 count rose from 210 to 491 in 8 years. People who interrupted treatment gained a median of 133 CD4 cells through 8 years, compared with 360 CD4s in group B and 395 in group C. Much higher proportions of people in groups B and C than in group A reached a CD4 count above 350 or above 500 during the study period (Table 1). Statistical analysis showed that the longer the antiretroviral interruption, the smaller the CD4 gain.

    Table 1. Proportions of Study Group Members Reaching a CD4 Count Above 350 or 500 in 8 Years

    Study group*Reached CD4 count above 350Reached CD4 count above 500
    Group A63%37.2%
    Group B76.3%55.8%
    Group C87.3%68%
    *See How the study worked for group definitions.

    Further statistical analysis identified several factors that raised or lowered the chance of reaching a CD4 count above 350 or 500, regardless of what other risk factors a person had:

    Predictors of reaching a CD4 count above 350:

    • Interrupting antiretrovirals lowered chances 20%.
    • Every 10 years of age lowered chances 11%.
    • HCV infection lowered chances 27%.
    • Female gender raised chances 17%.
    • Every 10 times higher pretreatment viral load raised chances 7%.
    • Every 100-cell higher pretreatment CD4 count raised chances 73%.

    Predictors of reaching of CD4 count above 500:

    • Interrupting antiretrovirals lowered chances 28%.
    • Every 10 years of age lowered chances 15%.
    • HCV infection lowered chances 20%.
    • HBV infection lowered chances 27%.
    • Every 100-cell higher pretreatment CD8 count lowered chances 2%.
    • An AIDS diagnosis raised chances 20%.
    • Every 10 times higher pretreatment viral load raised chances 10%.
    • Every 100-cell higher pretreatment CD4 count raised chances 70%.

    The overall rate of new CDC stage B diseases (relatively minor diseases like yeast infection and herpes zoster) was 11.9 per 1000 person-years. The rate was much higher in group A (15 per 1000 person-years) than in group B or C (8.1 and 9.2 per 1000 person-years). The overall rate of new CDC stage C diseases (major diseases like non-Hodgkin lymphoma and Pneumocystis pneumonia) was 11.3 per 1000 person-years. The rate was again higher in group A (14.8 per 1000 person-years) than in group B or C (8.1 and 7.4 per 1000 person-years). Rates of new CDC stage C diseases increased as the length of treatment interruption increased: 6% with interruptions less than 1 month, 10.4% with interruptions of 1 to 5 months, 10.7% with interruptions of 6 to 14 months, 13.9% with interruptions of 15 to 31 months, and 13.7% with interruptions longer than 31 months.

    Figure 1: Death rate with antiretroviral interruptions through 8 years.

    Figure 1. The death rate through 8 years of observation in the Swiss HIV Cohort Study was highest among people who interrupted antiretroviral therapy for at least 1 month (group A) and lower in people who did not interrupt treatment but had a viral load above 1000 copies at some point after 6 months of therapy (group B) and in people who did not interrupt treatment and always had a viral load below 1000 copies after 6 months of therapy (group C).

    The overall death rate during the 8-year study was 14.3 deaths per 1000 person-years. That rate was twice higher in group A (antiretroviral interrupters) than in group B or C (noninterrupters): 19.6 per 1000 person-years in group A versus 9.7 and 8.2 per 1000 person-years in group B and C (Figure 1). The rate of HIV-related death was also higher in group A (3.9 per 1000 personyears) than in group B or C (3.5 and 2.0 per 1000 person- years).

  • What the results mean for you. The findings of this large and long study in Switzerland add to what is already known about the risks of interrupting antiretroviral therapy. Earlier trials that randomly assigned people to interrupt or not interrupt treatment found higher rates of new AIDS and non-AIDS complications in people who took antiretroviral breaks.2-4 Unlike those studies, the new Swiss study1 is not a randomized trial. It is an ongoing observational study in which people with HIV and their doctors independently made decisions about their antiretroviral therapy and overall care. This kind of "observational cohort study" cannot rule out the possibility that factors not analyzed in the study affect results. But the Swiss HIV Cohort Study has one advantage over the three randomized trials: It tracked results for 8 years instead of 1 or 2.

    Over the 8-year study period, people who interrupted their antiretroviral pill taking for a month or more responded to therapy worse than noninterrupters in several important ways:

    • Antiretroviral interrupters had a lower chance of reaching a CD4 count above 350 or 500.
    • Interrupters had a higher chance of moderate and serious new AIDS diseases.
    • Interrupters had a higher risk of death from all causes.

    Sometimes it is necessary for a physician to interrupt a patient's antiretroviral therapy, for example, when some serious non-AIDS diseases develop. But major randomized trials and this Swiss HIV Cohort Study all found that interrupting antiretroviral therapy poses serious risks. You should never stop your antiretrovirals, unless your physician tells you to. If you believe your antiretrovirals are causing side effects you cannot tolerate, you should discuss those problems immediately with your doctor. Some side effects go away on their own after a short time. Or you may be able to switch to other antiretrovirals that are just as strong but do not cause side effects in you.

    The study also found that the risk of a new AIDS disease rose as the overall length of treatment interruption increased. Based on that finding, the Swiss team suggests that "if any treatment interruption is required, it should be as short as possible."

    Two other important findings emerged from this study: (1) People who started antiretroviral therapy at a higher CD4 count had a much better chance of reaching a CD4 count above 500 through 8 years of treatment, and (2) people who did not interrupt treatment and always had a viral load below 1000 copies after 6 months of therapy had the best overall responses. For these reasons, the Swiss researchers believe their results support starting antiretroviral therapy early in the course of HIV infection, avoiding treatment interruptions, and keeping the viral load as low as possible.


References

  1. Kaufmann GR, Elzi L, Weber R, et al. Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death. AIDS. 2011;25:441-451.
  2. Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet. 2006;368:459-465.
  3. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4 count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
  4. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981-1989.



This article was provided by The Center for AIDS. It is a part of the publication HIV Treatment ALERTS!. Visit CFA's website to find out more about their activities and publications.
 

 

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