CROI: Delaying HAART while treating opportunistic infections increases the risk of disease progression and death

Waiting to start combination antiretroviral therapy until after treatment of acute opportunistic or bacterial infections is associated with an increased risk of death compared with immediate HAART, according to a presentation Wednesday at the at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.

Antiretroviral therapy significantly reduces the risk of HIV disease progression and death in treated patients. Indeed, many HIV physicians are now optimistic that individuals who receive appropriate HIV therapy with good adherence could have a near-normal life expectancy.

HIV treatment guidelines, such as those of the British HIV Association, recommend that individuals who have symptomatic HIV disease should start antiretroviral therapy as soon as possible. However, there is no consensus about the optimal time to start anti-HIV therapy in patients with active opportunistic infections or serious non-opportunistic bacterial infections (OI/BIs). Some experts favour starting HAART immediately, but others advocate treating the other infections first in order to avoid the potential for increased side effects and drug interactions when combining antiretroviral and anti-OI/BI therapy.

Dr. Andrew Zolopa of Standard University and colleagues with the U.S. AIDS Clinical Trials Group study A5164 therefore conducted a Phase 4 treatment strategy trial to determine the optimal time of antiretroviral therapy initiation in patients with other acute infections.

The study involved 282 individuals with acute OI/BIs who were not taking antiretroviral therapy at baseline. They were equally randomised to start anti-HIV treatment either immediately or 14 days after completing treatment for their OI/BI. Patients with tuberculosis were excluded, since interactions between HAART and anti-TB drugs were poorly understood when the study began.

At baseline, patients in the two arms were similar. Most (85%) were men, with a median age of 38 years, and the group was of diverse race/ethnicity (37% black, 36% Hispanic, 23% white). Participants overall had advanced HIV disease and profound immune suppression at baseline, with a median viral load of 500,000 copies/ml and a median CD4 cell count of only 29 cells/mm³. Over 90% had never taken any anti-HIV drugs.

Participants were stratified according to baseline CD4 cell count (above or below 50 cells/mm³) and specific OI/BIs. The most common by a large margin was Pneumocystis pneumonia (PCP; 63%), followed by cryptococcal meningitis (16%) and bacterial pneumonia (12%). About one-third entered the study with more than one opportunistic or bacterial infection. Only diseases for which there is proven anti-infective therapy were included.

Patients started antiretroviral therapy after a median of twelve days in the immediate treatment arm and after a median of 45 days amongst patients who started anti-HIV drugs after completing OI/BI treatment. The antiretroviral drugs provided by the study were lopinavir/ritonavir (Kaletra), d4T (stavudine; Zerit), and tenofovir/emtricitabine (Truvada), but clinicians were free to use any standard combination regimen.

The primary study end-points were, at 48 weeks, death or HIV disease progression; no progression in HIV disease, but continued viral load above 50 copies/ml; or no disease progression and full viral load suppression below 50 copies/ml. Secondary end-points included various clinical outcomes, viral load and CD4 cell count changes, clinical and laboratory adverse events, hospitalisations, anti-HIV treatment adherence, and treatment switches.

Results showed that there were no significant differences in the primary end-points at 48 weeks between patients in the immediate and deferred antiretroviral therapy arms.

Of the participants who started anti-HIV treatment immediately, 14% died or experienced further HIV disease progression compared to 24% of those who deferred treatment (not a statistically significant difference. About one-third of patients (38% vs. 31%) in both arms experienced no HIV disease progression, but failed to suppress viral load below 50 copies/ml. The largest proportion of patients—approaching half in both arms (48% vs 45%)—had neither HIV disease progression nor detectable viral load at 48 weeks.

However, there were some important differences in outcomes between the two treatment strategies. As per the secondary end-point, patients who started anti-HIV treatment immediately were about half as likely to experience AIDS progression or death, and did so more slowly (odds ratio 0.51). There were fewer total deaths in the immediate therapy group, especially during the first six months of the study.

While immunological and virological responses at 48 weeks were not statistically different, patients in the immediate treatment arm achieved CD4 cell counts above 50 and above 100 cells/mm³ in less than half the time as those who delayed therapy, which was highly significant (eight vs. four weeks for > 50 cells/mm³, 12 vs. 4 weeks for > 50 cells/mm³).

Earlier initiation of antiretroviral therapy did not appear to be associated with any major risks. There was no significant difference in the incidence of moderate to serious (Grade 2-4) adverse events, frequency of hospitalisation, or days spent in hospital between the two study arms. The frequency of immune reconstitution inflammatory syndrome was similar in both arms and was uncommon overall, with eight cases in the immediate therapy arm and twelve amongst patients who deferred anti-HIV treatment.

Levels of adherence were high (over 90%) and similar in both arms, though the patients that started immediate anti-HIV treatment were more likely to change their antiretroviral regimen.

In conclusion, while there was a non-significant difference between the immediate and deferred antiretroviral therapy arms in terms of primary end-points that included both clinical and virological response, there was less AIDS progression and death in the immediate anti-HIV treatment arm, especially during the first six months.

Further, CD4 count increased more rapidly in the immediate treatment group, which the investigators characterized as reducing the “window of vulnerability” to AIDS progression or death.

“This randomized strategy trial suggests that, absent contraindications, consideration should be given to early use of antiretroviral therapy in HIV-infected patients presenting with an acute opportunistic infections,” the researchers recommended.