Background: Residual viraemia is a major obstacle to HIV-1 eradication in subjects receiving HAART. The intensification with raltegravir could impact latent reservoirs and might lead to a reduction of plasma HIV-1 viraemia (viral load [VL]), complementary DNA intermediates and immune activation. Methods: This was a prospective, open-label, randomized study comprising 69 individuals on suppressive HAART randomly assigned 2:1 to add raltegravir during 48 weeks. Results: Total and integrated HIV-1 DNA, and ultrasensitive VL remained stable despite intensification. There was a significant increase in episomal HIV DNA at weeks 2–4 in the raltegravir group returning to baseline levels at week 48. Median CD4 ⁺ T-cell counts increased 124 and 80 cells/μl in the intensified and control groups after 48 weeks ( P=0.005 and P=0.027, respectively), without significant differences between groups. No major changes were observed in activation of CD4 ⁺ T-cells. Conversely, raltegravir intensification significantly reduced activation of CD8 ⁺ T-cells at week 48 (HLA-DR ⁺ CD38 ⁺ , P=0.005), especially in the memory compartment (CD38 ⁺ of CD8 ⁺ CD45RO ⁺ , P<0.0001). Linear mix models also depicted a larger decrease in CD8 ⁺ T-cell activation in the intensification group ( P=0.036 and P=0.010, respectively). Raltegravir intensification was not associated to any particular adverse event. Conclusions: Intensification of HAART with raltegravir during 48 weeks was safe and associated with a significant decrease in CD8 ⁺ T-cell activation, and a transient increase of episomal HIV-1 DNA. However, raltegravir did not significantly contribute to changes in CD4 ⁺ T-cell counts, ultrasensitive VL, and total and integrated HIV-1 DNA. These findings suggest that raltegravir impacts residual HIV-1 replication and support new strategies to impair HIV-1 persistence. ClinicalTrials.gov identifier: NCT00554398.

To evaluate the expected activity of etravirine in clinical samples, according to mutational patterns associated with decreased virological response (VR). We identified 1586 routine clinical samples with resistance-associated mutations (RAMs) to nevirapine and efavirenz (K103N 60%, Y181C 37%, G190A 27%, V108I 13%). Concerning in vitro identified etravirine mutations, samples with F227C, Y181I, M230L or L100I plus K103N plus Y181C were considered highly resistant. Samples with two RAMs plus Y181C or V179D or K101E or Y188L were considered intermediate. The prevalence of 13 RAMs recently associated with decreased VR to etravirine in the DUET clinical trials was also investigated. Most samples (69%) harboured more than one IAS-USA RAM to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs): 42% harboured two RAMs, 21% three RAMs and 6% four or more RAMs. The prevalence of 13 specific etravirine RAMs was V179F 0.12%, G190S 3.9%, Y181V 0.1%, V106I 2.6%, V179D 1.6%, K101P 2.0%, K101E 10.1%, Y181C 36.9%, A98G 5.9%, V90I 6.9%, Y181I 3.6%, G190A 27% and L100I 9.1%. The five RAMs with the most impact on VR (V179F/D, G190S, Y181V and V106I) occurred less often. Overall, 8.2% of the samples had three or more etravirine RAMs and only 1.1% had four or more. In addition, patterns of RAMs previously associated with intermediate etravirine resistance were present in 26.2% of the samples, whereas 4.85% displayed patterns of high-degree resistance. For RAMs associated with decreased VR, etravirine resistance in routine clinical samples was lower than previously reported. High-degree resistance was uncommon, even in patients with resistance to first-generation NNRTIs, whereas low-to-intermediate etravirine resistance was more common.

Virological suppression rates achieved with the new antiretroviral drugs in patients with virological failure and resistance to multiple drug classes are nearly matching the rates seen in treatment-naive patients. Knowledge of cross-resistance patterns to drugs of the same class is key for successful use of etravirine, tipranavir, and darunavir in treatment-experienced patients. Determination of human immunodeficiency virus type 1 (HIV-1) tropism is cardinal for maraviroc. The impressive potency of raltegravir must not preclude its use with other active drugs because of its limited genetic barrier. These new agents have demonstrated superiority in virtually all efficacy parameters in their pivotal salvage trials, but comparative data between them are still very scarce. This review discusses the clinical implication of resistance to these new drugs. Specific genotypic resistance scores have been developed for tipranavir and etravirine, and mutations conferring resistance to darunavir are well understood. Determining the most active drugs and successfully combining them is the key challenge in salvage regimens.