CROI: SMART substudy finds people on treatment less likely to transmit HIV, and may take fewer risks

A substudy of sexually transmitted infections and sexual risk-taking among participants in the large SMART study of structured treatment interruptions has found that people on treatment breaks are more likely to have the kind of sexual encounters that pass on HIV, compared with people on continuous HIV therapy.

In part this was due to the unsurprising fact that patients on treatment interruptions spent a higher proportion of their time with raised viral load.

However the substudy also found, contrary to some expectations, that patients on antiretroviral therapy or who had taken it before were somewhat less likely to take sexual risks than people who had never taken antiretroviral therapy (ART).

This may counter fears that taking antiretroviral therapy may lead to ‘treatment complacency’. Although the SMART investigators did not ask participants why they modified their risk behaviour, they speculate that antiretroviral drugs may lower libido or that having a daily reminder of one’s status discourages behaviour founded on denial.

It’s important to note that the SMART risk behaviour substudy was only conducted in the United States, so its findings cannot necessarily be generalised to people from other countries.

SMART, as the study is generally known, was a large controlled trial in which patients were randomised to take continuous antiretroviral therapy or to interrupt therapy when their CD4 cell count rose above 350 cells/mm³ and resume it only when it fell below 250 cells/mm³. It was stopped in late 2005 when investigators found that patients in the treatment-interruption arm had a significantly higher risk of progressing to AIDS or of dying from any cause.

In terms of the whole study, 2,572 patients took continuous therapy and spent 91% of their time on antiretrovirals; 2,720 people took treatment interruptions and spent 38% of their time on antiretrovirals.

The number of patients in the risk behaviour substudy was 883 out of an originally planned size of 1,010, with 443 patients on continuous therapy and 440 on treatment interruptions.

The vast majority were either on ART or had taken it before they entered the study: only 7% (62 patients) were ART-naïve but, as we will see, these formed an important subgroup.

The patients were quite old, with an average age of 45. A quarter of them were women, 46% were African-American and 52% said their risk factor for HIV was male-male sex. Sixteen per cent had shared needles.

At trial entry their average CD4 count was 555 cells/mm³ and 54% had a viral load below 400 copies/ml.

In terms of their baseline risk behaviour, 58% had had sex of any kind over the previous two months but only 14% had had unprotected sex with someone who was or might have been HIV-negative while another 1.4% had shared needles with someone who was or may have been HIV-negative over the last two months, totalling 15.4% who had indulged in ‘risky behaviour’.

There was more risky behaviour at baseline in the 62 trial participants who were naïve to ART at trial entry: 20% of them had had risky behaviour over the previous two months compared with 14% of drug-experienced patients.

Only 6.85% of trial participants had had risky behaviour during times their viral load was over 1,500 copies, a threshold determined as posing a significant risk of HIV transmission by the SMART investigators, based on a study of HIV transmission within heterosexual couples in Uganda.

Being in the continuous therapy arm of the trial seemed to confer a slight but non-significant decrease in risk behaviour, though this was not sustained. At four months into the trial, 13.4% of patients in the drug-interruption arm showed risky behaviour versus 10.4% of patients in the continuous therapy arm, though this difference grew less over time, and at no point was the difference in risky behaviour between the two trial arms statistically significant.

The main reason for the difference that was observed was an immediate halving of risk behaviour, from 20% at baseline to 10% at four months (and 13% at twelve months), in the minority of patients in the continuous-therapy arm who started ART for the first time when they entered the SMART study. In contrast, drug-naïve patients who were randomised to the drug-interruption arm (and who therefore would not have immediately started therapy) actually showed a slight increase in their risk behaviour at four and twelve months. The difference between the trial arms in the case of naïve patients was statistically significant at months four and twelve, but not by month 24.

There was, unsurprisingly, a continuously significant difference between the trial arms in the proportion of patients who had risky behaviour while their viral loads were over 1,500 copies/ml. At month four the proportion having unprotected sex or sharing needles with a viral load over 1,500 copies/ml was 10.8% on the drug-interruption arm and 4.5% on the continuous-therapy arm, 12.4% and 5.4% at month twelve and 11.0% and 5.3% at month 24. The risk of doing this with a person who was or might be HIV-negative was 4-6% at all time points in the drug-interruption arm and 1-2% in the continuous-therapy arm. Being in the drug-interruption arm therefore probably more than doubled the risk of being in a position to transmit HIV.

“Because HIV RNA levels were higher overall among patients on episodic therapy, this strategy may result in increased HIV transmission to partners,” comment the SMART investigators.