There is no magic formula for achieving 10 years of continuous viral load suppression on antiretroviral therapy in people living with HIV -- even perfect adherence didn't improve the chances of continuously suppressed viral loads, according to a poster analysis of the U.S. Military HIV Natural History Study (NHS) cohort presented at IDWeek 2014 in Philadelphia.
Rather, in the multivariate analysis, failure to achieve 10 years of continuous suppression was associated with factors before treatment was initiated -- namely, being diagnosed before the antiretroviral therapy era, receiving mono or dual antiretroviral therapy before first starting a "highly active" antiretroviral therapy regimen, and having a higher viral load when starting the first regimen. In addition, those who have not maintained 10 years of continuous viral load suppression tend to have taken a higher number of antiretroviral therapy regimens -- but this is more likely a consequence of viral failure than the cause of it.
Sustained viral load suppression -- which is necessary for immune reconstitution, reduction in AIDS events, and improved lifespan -- is the goal of antiretroviral therapy. However, many studies suggest this is hard to achieve, occurring in only 60% to 80% of individuals in cohort studies, and in approximately 85% in clinical trials, at best.
A number of factors have been associated with failure to achieve and sustain viral suppression, including suboptimal adherence, adverse effects of antiretrovirals, and drug-resistance mutations.
But given the range of antiretroviral therapy options today, it is unclear whether the failure or poor tolerability of one regimen will be associated with continued inability to achieve sustained virologic suppression, or what factors might be associated with continuous suppression (such as specific regimens or perhaps perfect adherence).
The NHS Study
To assess factors associated with continuous viral load suppression in individuals over a follow-up of at least 10 years, Kathryn Bello, D.O., and colleagues from the Uniformed Services University of the Health Sciences looked at the experience of participants in the NHS, which is an observational cohort being followed at seven Department of Defense medical treatment facilities in the U.S. The cohort has been enrolling since 1986 and includes more than 5,700 participants. Self-reported adherence data have been gathered in the cohort since 2006.
To be included in the analysis, participants had to have a documented date of HIV diagnosis, have CD4 and viral load values at antiretroviral therapy initiation and at least yearly thereafter, and have been taking antiretroviral therapy for 10 years or more (though treatment interruptions of less than 6 months were permitted).
Viral load suppression (VS) was defined as having viral load less than 400 copies/mL within one year of the first antiretroviral therapy regimen. Virologic failure (VF) was defined as not achieving a viral load less than 400 copies/mL within one year or having two consecutive viral loads greater than 400 copies/mL after initial suppression.
For the analysis, 276 qualifying participants were divided into two groups:
- Continuous suppression (CS), meaning all viral load values greater than 400 copies/mL for more than 10 years (149 participants).
- Non-continuous suppression (NCS), meaning experienced more than 1 VF episode over 10 years (127 participants).
- The vast majority of the participants were male who were around the age of 31 at diagnosis, and started antiretroviral therapy around age 37.
- About 11% of the participants were Hispanic, 43% were white, and 46% were black. In the multivariate analysis, the non-white participants were roughly half as likely as the white participants to achieve CS -- but these findings did not reach statistical significance.
- The median year of diagnosis was significantly earlier (1991) in those with NCS; it was 1996 in those with CS.
- The era in which antiretroviral therapy was initiated also was significantly associated with success or failure. About 90% of those with NCS started antiretroviral therapy between 1996 and 1999, versus 60% of those with CS. Those who started between 2000 and 2003 were about three times more likely to achieve CS than to fail.
- Those who achieved CS had significantly higher median CD4 counts at baseline than those with NCS (375 versus 261).
- Median baseline viral loads were lower in those who achieved CS versus NCS. In the multivariate analysis, having a higher baseline viral load was significantly more likely.
- Prior AIDS status was not significantly associated with CS suppression in the multivariate analysis.
- About 63% of the participants started their first antiretroviral regimen with a non-boosted protease inhibitor -- which seemed to be associated with more NCS (76%) than CS (51%) in the univariate analysis (though this did not bear out in the multivariate analysis).
- Taking antiretrovirals prior to initiating a highly active antiretroviral therapy regimen was significantly more common among those with NCS (83%). Only 37% of those who achieved CS had prior antiretroviral history.
- Those who achieved CS reached initial VS more rapidly than those with NCS (0.22 years versus 0.47 years; P < 0.001).
- The study also observed that CS is the key to good CD4 reconstitution, with increased CD4 recovery post-antiretroviral therapy as seen in those with CS (up to 701) versus NCS (up to 508).
- Participants with NCS had a higher proportion of new AIDS events by 10 years of highly active antiretroviral therapy (13% versus 5%; P = 0.033) and used a greater number of regimens during follow-up (7 versus 3; P < 0.001) compared to CS participants.
- Perfect adherence appeared to make little difference in outcomes, as the self-reported average adherence was 98 to 99%.
It must be pointed out that this study would appear to have at least one major limitation: a survival bias. Some individuals who don't achieve sustained virologic suppression die or are lost to follow-up before 10 years have passed. If their data were included in the analysis, and treated as NCS, some of the more borderline associations might change in significance -- and differences between perfect (or very good) adherence versus the true average adherence among the NCS participants might emerge.
The data suggest that in the current era, if treatment is started early enough, CS should be possible -- even if it takes a switch or two to achieve it (given those with CS had been on approximately three regimens).
Furthermore, Bello, who presented the poster, and her colleagues don't feel that all hope is lost for people who have failed to achieve continuous suppression. "Newer regimens have higher viral suppression rates which may mitigate the negative factors of [pre-antiretroviral therapy] era diagnosis and treatment," the researchers concluded.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience. You can follow him on Twitter @theosmart.