Meta-analysis shows superiority of integrase inhibitors in first-line HIV therapy and benefits for people changing treatment due to resistance

Antiretroviral combinations based on an integrase inhibitor are superior to other first-line HIV treatment regimens, according to the results of a meta-analysis published in the open access journal PLoS One. The study also showed the benefits of integrase inhibitor-containing regimens for people changing HIV therapy after virological failure. However, switching to an integrase inhibitor was not supported for people whose existing therapy was suppressing viral load.

“The addition of the integrase inhibitor class to our armamentarium has strengthened cART [combination antiretroviral therapy] regimens, and further rational use can preserve future therapeutic options,” write the authors.

Integrase inhibitors are a class of anti-HIV drug that prevent the integration of the virus into CD4 cells. The first integrase inhibitor to be approved was raltegravir (Isentress). Other drugs in this class have been, or are being, developed. Elvitegravir has been licenced in the United States and clinical studies involving dolutegravir are well advanced.

Originally envisaged as a therapy for people with previous experience of HIV treatment and drug-resistant strains of HIV, integrase inhibitors are also considered an option for individuals who are starting antiretroviral therapy.

However, the precise benefits of therapy with an integrase inhibitor are unclear. Investigators from Belgium and the Netherlands therefore performed a systematic review and meta-analysis of current evidence for the use of integrase inhibitors in a variety of patient populations.

Studies published or presented between 2006 and 2012 were included in the study if they compared the virological efficacy of a regimen containing an integrase inhibitor to that of a combination based on a different class of antiretrovirals.

The effectiveness of integrase inhibitors was examined in three patient populations: treatment-naive individuals; people changing therapy due to virologic failure; and those switching treatment in the context of a suppressed viral load.

A total of 16 studies met the inclusion criteria.

The meta-analysis was performed using modified intent-to-treat (mITT), on-treatment (OT) and as-treated (AT) data.

A review of the ten studies involving treatment-naive patients showed that use of an integrase inhibitor achieved better virologic outcomes. These reached significance in the mITT (OR = 0.71; 95% CI, 0.59-0.86) and OT (OR = 0.63; 95% CI, 0.47-0.84) analyses. The AT data showed a non-significant trend favouring integrase inhibitor-containing regimens (OR = 0.86; 95% CI, 0.61-1.22).

A sub-analysis compared first-line integrase inhibitor-based therapy to treatment based on the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva, also in Atripla). Both the mITT (OR = 0.67; 95% CI, 0.54-0.84) and OT (OR = 0.59; 95% CI, 0.43-0.81) data showed the superiority of the combinations that included an integrase inhibitor. The investigators suggest this superiority was due to the good toxicity and safety profile of integrase inhibitors. 

Results from three studies involving treatment-experienced patients with virological failure were included examined by the investigators. The mITT results favoured the use of an integrase inhibitor (OR = 0.27; 95% CI, 0.11-0.66). Meta-analysis of two studies using both OT data (OR = 0.28; 95% CI, 0.20-0.38) and AT data (OR = 0.16; 95% CI, 0.04-0.61) confirmed this finding.

Next, the investigators turned their attention to outcomes among treatment-experienced patients who had an undetectable viral load when they switched to an integrase inhibitor. Three studies were included in this meta-analysis. In the mITT analysis, there was a non-significant trend suggesting the inferiority of integrase inhibitor-based therapy (OR = 1.43; 95% CI, 0.89-2.31). The AT analysis clearly showed inferiority of integrase inhibitors (OR = 1.73; 95% CI, 1.01-2.97) when patients were switching from boosted protease inhibitors.

“Based on the meta-analysis, treatment with INIs [integrase inhibitors] in combination with dual NRTIs [nucleoside reverse transcriptase inhibitors] showed to be more beneficial for treatment-naïve patients compared to other currently used treatment strategies,” conclude the authors. “Also in treatment-experienced patients with virological failure, use of INIs proved to be beneficial as well. However, in successfully treated patients…switching a high genetic barrier drug towards INI was not supported.”

Messiaen P et al. Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis. PLoS One, 8 (1): e52562, 2013