NRTI-sparing combination of darunavir/ritonavir and raltegravir not a good option for patients with high viral load

An HIV treatment combination comprising ritonavir-boosted darunavir and raltegravir has “acceptable” virological efficacy, but may be a poor option for patients with a high viral load, US investigators report in the online edition of AIDS.

Resistance to raltegravir emerged in some patients with low levels of detectable virus, “an important observation”, write the investigators, “since recent guidelines state that VL [viral load] > 200 copies/ml can be considered the threshold for VF in clinical practice.”

Since 1996 antiretroviral therapy has been based on a “backbone” of two nucleoside reverse transcriptase inhibitors (NRTIs). However, many of the side-effects of HIV therapy are associated with NRTI.

Two drugs may be enough to achieve durable suppression of HIV, and a combination consisting of the ritonavir-boosted protease inhibitor darunavir (Prezista) and the integrase inhibitor raltegravir (Isentress) is being investigated in clinical trials.

One of these is the US ACTG A5262 study. It recruited 112 HIV-positive individuals who were starting antiretroviral therapy for the first time.

They were treated with an open-label regimen of ritonavir-darunavir 800/100mg once daily a twice-daily dose of 400mg of raltegravir.

The primary endpoint of the study was the proportion of patients with virological failure at or before week 24.

This was defined as a viral load of 1000 copies/ml or above at week twelve; a 0.5 log₁₀ increase in viral load between weeks four or twelve; or a viral load above 50 copies/ml at week 24. On the basis of earlier research, a failure rate of 35% at week 24 was considered acceptable.

Secondary endpoints included the proportion of patients with viral suppression at week 48; the emergence of resistance; changes in CD4 cell count; and safety.

Most (88%) of the patients were men and their median age was 36 years.

Baseline median CD4 cell count was 271 cells/mm³ and median viral load at the start of therapy was 4.87 log₁₀ copies/ml. Many patients had a high pre-treatment viral load, including 44% with a viral load above 100,000 copies/ml and 5% with a viral load above 750,000 copies/ml.

The overall rate of virological failure at week 24 was 16% (n = 17).  By week 48 the failure rate had increased to 26% (n = 28).

In an intent-to-treat analysis that included all patients enrolled in the study regardless of withdrawal or treatment modification, 74% of patients had an undetectable viral load at week 24 and 61% at week 48.

Patients experiencing virological failure had a higher baseline viral load than individuals with virological suppression (median 5.22 log₁₀ copies/ml vs. 4.70 log₁₀ copies/ml; p = 0.002). They also had a lower median CD4 cell count at the start of therapy (192 vs. 322 cells/mm³; p = 0.007).

Of the 28 patients with virological failure, 21 had a baseline viral load above 100,000 copies/ml.

Statistical analysis adjusting for age and sex showed that virological failure was associated with a baseline viral load above 100,000 copies/ml (hazard ratio [HR] = 3.76; 95% CI, 1.52-9.31; p = 0.004). CD4 cell count was also significant,  and each 100 cell/mm³ increase in baseline count reduced the risk of virological failure by 33% (HR = 0.77, 95% CI, 0.61-0.98; p = 0.037).

A viral load above 100,000 copies/ml remained a significant predictor of treatment failure when trough concentrations of raltegravir were also included in the analysis (p < 0.001). Moreover, having undetectable plasma levels of raltegravir on at least one occasion was also associated with failure to suppress viral load (p = 0.006).

A total of five patients developed resistance to raltegravir. Their viral load ranged from 62 to 685 copies/ml, indicating that “raltegravir resistance mutations may be present at low level viremia.”

CD4 cell counts had increased by a median of 142 cells/mm³ at week 24 and 200 cells/mm³ at week 48. Patients with a baseline viral load below 100,000 copies/ml had more robust increases in CD4 cell count at week 48 than patients with higher viral loads (233 vs. 180 cells/mm³; p = 0.044).

The combination appeared safe. Approximately a fifth of patients developed a grade 3 or higher clinical or laboratory event. Only one patient stopped treatment because of side-effects, a rash and stomach pains.

The investigators conclude their results “raise important issues that should be examined carefully in future studies evaluating darunavir/ritonavir plus raltegravir and perhaps in all NRTI-sparing two-drug regimens.”

They urge caution in patients with baseline VL > 100,000 copies/ml and emphasise "a need to further elucidate the implications of low-level viremia in patients receiving this regimen.”

Taiwo B et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir plus raltegravir in treatment-naïve HIV-1-infected patients (ACTG A5262), online edition, doi: 10.1097/QAD.0b013e32834bbaa9 (free abstract available here).