The latest analysis of data from the SMART study suggest that HIV-positive people who periodically interrupt therapy based on CD4 cell counts have a slightly higher risk of heart problems, according to a presentation on Monday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.
The SMART (Strategies for Management of Anti-Retroviral Therapy) Study, sponsored by the US National Institutes of Health, compared the safety and efficacy of two antiretroviral treatment strategies: CD4-guided intermittent therapy (drug conservation arm) or continuous therapy (viral suppression arm). In the intermittent therapy arm, participants went (or stayed) off treatment while their CD4 cell counts remain above 350 cells/mm3, and resumed when counts fell below 250 cells/mm3.
A total of 5,472 participants enrolled in the study and were randomly assigned to one of the two arms. All had baseline CD4 cell counts above 350 cells/mm3, 85% were currently on antiretroviral therapy, and 95% had used antiretroviral therapy at some time. Overall, the study population had several risk factors for heart disease: the median age was 44 years, 73% were men, 40% were smokers, 19% were taking blood pressure drugs, and 16% were taking lipid-lowering medications.
The study was terminated early, in January 2006, after an interim analysis revealed that participants in the intermittent therapy arm were more likely to experience disease progression or death. Results were published in the November 30th, 2006 edition of the New England Journal of Medicine.
Unexpectedly, participants in the treatment interruption arm not only had a higher rate of AIDS-related illnesses, but also were more likely to experience complications thought to be related to antiretroviral therapy, such as cardiovascular, liver, and kidney problems. Participants in the treatment interruption arm had a significantly higher risk of serious complications including heart attacks, strokes, and kidney or liver disease (2.1%), compared with those on continuous therapy (1.4%).
To shed further light on these findings, Professor Andrew Phillips and colleagues conducted an exploratory analysis comparing the risk of cardiovascular events between the two arms, and also looked at associations with different classes of antiretroviral drugs: nucleoside/nucleotide reverse transcriptase inhibitors (NTRIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).
Out of the 5,472 trial participants, 79 (1.4%) developed major cardiovascular events, including death, non-fatal heart attacks, “silent” myocardial infarctions revealed by EKG monitoring, strokes, coronary artery disease, or need for related procedures. There were 48 total events in the intermittent treatment arm and 31 in the continuous therapy arm. When the risk in the two arms was compared, the intermittent therapy group had a hazard ratio (HR) of 1.57, or 1.5 times the risk. In terms of specific outcomes, there were seven cardiovascular deaths in the intermittent therapy arm and four in the continuous therapy arm; twelve participants in each group experienced non-fatal heart attacks.
The researchers then looked at the subset of participants who were on antiretroviral therapy at beginning of study; 43% were on NNRTI-based regimens and 45% were taking PI-based regimens. Those using intermittent therapy had a HR of 1.37, but risk differed with type of drugs used. Compared with PI-based regimens, NRTI-only regimens had a HR of 1.78, while NNRTI-based regimens were associated with roughly double the risk of cardiovascular events (HR 2.07). Notably, participants whose baseline regimens including the NNRTI nevirapine (Viramune) had a HR of 9.29.
In the continuous therapy arm, researchers noted an increase in the risk of cardiovascular events per additional year of exposure to PI-based – but not NNRTI-based -- regimens (HR 1.17), which is consistent with findings from the large D:A:D study. However, this was not seen in the intermittent therapy arm, suggesting that stopping therapy may reduce the cardiovascular impact of PIs.
Amongst the 16% of participants who were not on antiretroviral therapy at the start of the study, the HR for cardiovascular events was 4.41. There was no evidence that currently being off treatment, current higher HIV viral load, or current lower CD4 cell count were significantly associated with increased cardiovascular risk.
Because the total number of cardiovascular events was small, the difference between the two treatment strategy arms achieved only marginal statistical significance. But when the researchers looked at blood lipid changes – a clear predictor of cardiovascular risk in the general population – the differences were more definitive.
After the first year, total and low-density lipoprotein (LDL) cholesterol levels were lower amongst participants on intermittent therapy, suggesting a decreased risk of cardiovascular disease. However, rates of protective high-density lipoprotein (HDL) were also lower, indicating a potentially increased risk. Looking at the ratio of these two measures, the benefits of decreased total and LDL cholesterol appeared to outweigh the risk of reduced HDL, especially amongst participants on NRTI-only or nevirapine regimens.
The researchers concluded that in the SMART study there was a “marginally statistically significant raised risk of major cardiovascular events” among participants assigned to receive CD4-guided intermittent therapy. This finding remained consistent when they repeated the analysis using an expanded definition of cardiovascular endpoints.
They noted that while there was “no evidence that interruption immediately increases risk of cardiovascular disease,” longer-term consequences remain to be determined. In the meantime, according to Phillips, the data suggest that antiretroviral therapy should not be stopped or avoided due to concerns about perceived cardiovascular risk.
Phillips A et al. Interruption of ART and risk of cardiovascular disease: findings from SMART. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 41, 2007.
El-Sadr W et al. CD4+ count-guided interruption of antiretroviral treatment. New England Journal of Medicine 355: 2283-2296, 2006.