Breaks from HIV therapy still associated with poorer outcomes 8 years later

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HIV-positive patients who take breaks from their antiretroviral therapy have poorer increases in their CD4 cell count, are more likely to develop HIV-related illness, and have a higher risk of death than individuals who take continuous treatment, and these risks persist for at least eight years after the treatment break, Swiss investigators report in the online edition of AIDS.

The research also showed that longer breaks from treatment were associated with especially poor outcomes.

“The results strongly support the concept that patients should be discouraged to discontinue antiretroviral therapy,” comment the investigators.

Glossary

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

oral

Refers to the mouth, for example a medicine taken by mouth.

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

plasma

The fluid portion of the blood.

There have been significant improvements in HIV therapy in recent years, and the prognosis for many patients is now considered normal.

However, large numbers of patients taking antiretroviral drugs interrupt their treatment. The SMART study showed that treatment interruptions were associated with an increased risk of illness and death from both HIV-related and non-HIV-related illnesses.

But follow-up in the SMART study was relatively short (median 22 months). Because HIV treatment is life-long, Swiss investigators wished to see the implications of treatment interruptions in patients taking long-term antiretroviral therapy.

Their study population comprised 2491 individuals who started HIV treatment between 1996 and 2008.

They were divided into three groups according to their use of treatment and outcomes.

The first group (51%) comprised patients who interrupted their treatment at least once. The second (19%) included those who took continuous therapy but who sometimes had a viral load above 1000 copies/ml. The final group of patients were those who took uninterrupted therapy and maintained a viral load below 1000 copies/ml.

Over a median of seven years of follow-up, changes in CD4 cell count, rates of HIV-related illness and mortality rates were compared between the three groups.

Average CD4 cell count increased from 210 cells/mm3 at baseline to 491 cells/mm3 after eight years. However, CD4 cell gains differed significantly between the three groups of patients.

Only 63% of patients who took a treatment break had an increase in their CD4 cell count to above 350 cells/mm3. This compared to 73% of those who took continuous therapy and occasionally had a viral load above 1000 copies/ml and 87% of individuals who took continuous therapy with good viral suppression (p < 0.001 for both comparisons).

Patients who interrupted their therapy were also significantly less likely to have an increase in their CD4 cell count above 500 cells/mm3 (37% vs. 56% vs. 68%, p < 0.001).

Individuals who took the longest treatment breaks had the poorest increases in their CD4 cell counts (p < 0.001). Indeed, individuals whose interruption lasted 31 months or more had a slight fall in their CD4 cell count from baseline.

Statistical analysis showed that patients who interrupted therapy were significantly less likely to achieve either a CD4 cell count above 350 cells/mm3 (p = 0.001) or above 500 cells/mm3.

Other factors associated with CD4 cell count increases to below these levels included older age (p= 0.001 and p < 0.001 respectively),  co-infection with hepatitis C virus (p < 0.001 and p < 0.003) and starting HIV treatment at a lower CD4 cell count (p < 0.001 for outcomes).

Taking treatment breaks also had clinical significance. HIV-related illnesses such as oral hairy leukoplakia, oral thrush, and herpes were more common in those who interrupted therapy and the other two groups of patients (p = 0.013 and p = 0.034 respectively).

Similarly, individuals who stopped treatment were more likely to develop an AIDS-defining illness than those who took continuous treatment and had occasional viral load above 1000 copies/ml (p = 0.001) and individuals taking therapy all the time with viral suppression (p < 0.001).

Longer duration of treatment interruption was also associated with poorer outcomes. A total of 6% of patients who took a treatment break lasting under a month developed an AIDS-defining illness, and this increased to 11% for those taking breaks lasting over six months and 14% among those whose interruption lasted 31 months or more.

“If any interruption is required, it should be as short as possible to avoid poor clinical outcomes,” comment the investigators.

Mortality rates were highest among patients who interrupted therapy (20 per 1000 person years) and lowest for those whose treatment was continuous and suppressed viral load to below 1000 copies/ml (8 per 1000 person years). In addition, HIV-related mortality was 4 per 1000 person years for those interrupting therapy, but just 2 per 1000 person years when therapy was taken without interruption and was virologically suppressive.

Unlike the SMART study, the investigators found no evidence that treatment interruptions increased the risk of death from cardiovascular disease, rates of which were similarly low in all three groups of patients.

“The absolute risk of cardiovascular events remained low,” the researchers note.

The investigators believe their study “adds important new information on the long-term clinical consequences of treatment interruptions and the effect of duration of treatment interruptions.” They write that their findings show “an interruption of ART for 6 months or more resulted in sub-optimal recovery of CD4 T lymphocytes and increased risk of opportunistic complications or death.”

To achieve the best outcomes in patients the authors suggest “it appears to be essential to initiate ART early, avoid treatment interruptions and suppress plasma HIV-1 RNA to values as low as possible."

References

Kaufmann GR et al. Interruptions of cART limits CD4 T-cell recovery and increases the risk of opportunistic complications and death. AIDS 25: online edition (DOI: 10. 1097/QAD.0b013e32834360013), 2011 (for access to the study’s free abstract, click here).