Etravirine, darunavir/ritonavir and raltegravir very effective in highly treatment-experienced patients

A combination of raltegravir, etravirine and darunavir/ritonavir is highly effective at suppressing viral load to undetectable levels in treatment-experienced patients, French investigators report in the November 1^st edition of Clinical Infectious Diseases.

All 100 patients in the 48-week, prospective, non-comparator study had multiple resistance mutations to protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs). Nevertheless, after a year of treatment with the three new drugs, 86% had a viral load below 50 copies/ml.

“Patients infected with highly-resistant HIV and who have few remaining treatment options may benefit from an antiretroviral regimen containing raltegravir, etravirine and darunavir/ritonavir and may achieve virologic suppression similar to that of treatment-naïve patients,” write the authors.

Antiretroviral treatment for patients with extensive resistance to anti-HIV drugs is most effective if it includes two, and preferably three, drugs that have significant anti-HIV activity.

However, until recently, treatment for patients with drug resistance was often limited because it was only possible to introduce one new drug, which was used in combination with the best possible combination of other drugs selected after resistance testing (frequently called optimised background therapy).

New classes of antiretroviral drugs have recently become available, as have more potent drugs in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) classes that have a high level of activity against drug-resistant virus.

French investigators wished to determine the safety and effectiveness of the integrase inhibitor raltegravir (Isentress), the NNRTI etravirine (Intelence), and the ritonavir-boosted protease inhibitor darunavir (Prezista) in 100 patients with extensive resistance to existing anti-HIV drugs.

The patients were recruited from hospitals across France in 2007. Resistance tests conducted on entry to the study showed that the patients had a median of four mutations conferring resistance to protease inhibitors, six mutations associated with resistance to NRTIs and one NNRTI resistance mutation.

This resistance profile was acquired over an average of 13 years of antiretroviral therapy.

A total of 90 patients took the three study drugs with optimised background therapy, for example two "recycled" NRTIs or the fusion inhibitor T-20 (enfuvirtide, Fuzeon).

After 24 weeks of treatment, 90% of patients had a viral load below 50 copies/ml, and at 48% weeks, 83% of individuals still had a viral load below this level.

Viral load was rapidly suppressed, with 55% having an undetectable viral load after four weeks of therapy and 88% after twelve weeks.

The median increase in CD4 cell count by week 48 was 108 cells/mm³.

Few patients experienced HIV disease progression during the study, there being only two new AIDS-defining events. One patient died; however, this was not related to the study medication and involved a heart attack following heart surgery.

Only 4% of patients experienced clinical side-effects thought to be related to the study drugs, and only one patient stopped treatment because of these (a rash caused by raltegravir).

Moderate-to-severe laboratory abnormalities were observed in 19% of patients, but none of these were serious enough to warrant the amendment or discontinuation of therapy.

“Patients infected with multidrug-resistant HIV who have few remaining treatment options showed high rates of virologic suppression and favourable immunological outcomes at 48 weeks with a combination antiretroviral regimen containing raltegravir, etravirine, and darunavir/ritonavir,” comment the investigators.

Although 90 patients utilised additional drugs as optimised background therapy, the investigators write “we did not find any trends showing that optimised background therapy offers additional benefits.”

The study did not include a control arm. Nevertheless, the study’s authors write “we believe that the benefits of this combination for patients infected with multidrug-resistant HIV are sufficiently great to make interpretation of our results unambiguous. Therefore, treatment with raltegravir, darunavir/ritonavir, and etravirine may be recommended for patients harbouring multidrug-resistant virus, and the study results suggest an additional randomised control trial would not be needed to evaluate this combination.”