Should patients with high viral loads and high CD4 cell counts start anti-HIV therapy? (corrected)

Analysis of data from a large Canadian study has found that having viral load above 100,000 copies/ml before starting antiretroviral therapy is only associated with an increased risk of death in HIV-positive patients who are not adherent to their treatment regimen. The study’s investigators use this finding to question the recommendation that patients with high viral loads should start anti-HIV treatment regardless of their CD4 cell count. The findings were published in the 12^th May edition of AIDS.

Current HIV treatment guidelines recommend that HIV-positive patients start taking treatment when their CD4 cell count is between 200 and 350 cells/mm³. However, they also recommend that patients with viral loads above 100,000 copies/ml start anti-HIV treatment, even if they have a CD4 cell count above 350 cells/mm³.

Although the link between baseline CD4 cell counts and the risk of disease progression and death is well established, the evidence for increased mortality after starting treatment in patients with high viral loads is less strong. In addition, the interaction between viral loads and adherence after starting anti-HIV therapy has received little attention.

To examine the impact of high viral loads, investigators from the Highly Active Antiretroviral Therapy Observational Medical Evaluation and Research (HOMER) study examined the death rates of 1166 patients starting antiretroviral therapy with a CD4 cell count above 200 cells/mm³.

They found that having a baseline viral load above 100,000 copies/ml was not associated with an increased death rate in the 650 patients who were more than 95% adherent to their treatment regimen, over a median of 50.4 months (p = 0.690).

In contrast, high baseline viral load was linked to an increased death rate in the 516 non-adherent patients (p = 0.032). Adherence was measured by monitoring how often the patients returned for repeat prescriptions in the first year of treatment: the researchers note that this is a conservative measure of actual adherence levels.

The investigators confirmed that viral load was not significantly associated with the risk of death using a multivariate analysis that corrected for adherence (p = 0.232). This result was also unaffected by discounting the patients who died through accidents and those who had an AIDS diagnosis before starting treatment.

“Plasma HIV ribonucleic acid (RNA) greater than or equal to 100,000 copies/ml is only associated with mortality when the CD4 cell count is greater than 200 cells/mm³ among patients who are non-adherent,” they conclude.

“These findings are likely explained by elevated HIV disease progression among patients who have a worse baseline plasma HIV RNA profile and who are non-adherent”, they add, noting that more of the adherent than non-adherent patients had viral loads below 500 copies/ml during the first year of treatment (p

The investigators question the recommendation that patients with a high viral load should start antiretroviral therapy regardless of CD4 cell count. “Our findings indicated that highly active antiretroviral therapy (HAART) should be delayed in favour of adherence-readiness interventions in these patients, as the plasma HIV RNA level is of negligible prognostic value among adherent patients with baseline CD4 cell counts greater than or equal to 200 cells/mm³,” they write.

This is echoed in an accompanying editorial comment by Prof Cristina Mussini of the University of Modena and Reggio Emilia: “The message from this study is important. Clinicians should not be scared by elevated HIV RNA values since their detrimental effect on patients’ prognosis could be outweighed as long as HAART regimens are taken correctly.

“Since adherence to treatment is the most important prognostic factor and it is difficult to maintain for long periods of time, there is no reason why patients with high HIV RNA should be proposed treatment in presence of a CD4 lymphocyte count higher than that recommended by international guidelines,” she adds.

However, she warns that doctors may need to guess how adherent a patient will be before they start treatment. “A possible limitation of the clinical value of these findings is that it requires clinicians to be able to make an accurate assessment of a patient's likely adherence on therapy," she writes. "Published studies have shown that clinicians’ preconceptions about patient adherence are likely to be incorrect, and that they should not use this information when deciding when making their decision about when to start therapy.

“Patients more than guidelines should be the centre of our prescription. Indeed, antiretroviral therapy should be started when the patient is ready to take it correctly and it should be tailored […] to the patient’s lifestyle, to improve, at least in theory, adherence.”