Virological and immunological response to HAART regimen containing integrase inhibitors in HIV-2-infected patients

HIV-2 is naturally resistant to current non-nucleoside reverse transcriptase inhibitors and fusion inhibitors [1]. Moreover, compared with HIV-1, lower in-vitro susceptibility of HIV-2 to several protease inhibitors (PI) [2,3], and weak in-vivo immunological responses to triple combined antiretroviral therapy (ART) and classic PI-containing regimens have been previously reported [4,5]. Therapeutic options in the case of immunovirological failure after several ART lines are therefore limited. Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, phenotypic susceptibility to the two available integrase inhibitors (INI) is similar to that of HIV-1 [6]. We report the virological and immunological response to a HAART regimen containing INI in two HIV-2-infected patients experiencing immunovirological failure to several ART lines. The clinical outcome, plasma HIV-2-RNA viral load and CD4 cell count were recorded at initiation of treatment, and months 1, 3 and 6. The viral load was measured using an ‘in-house’ real-time polymerase chain reaction assay previously described [7,8]. For plasma obtained before 2001, HIV-2 plasma RNA was quantified retrospectively using the same assay. The first patient was a 56-year-old symptomatic HIV-2-infected man originating from Mali, who had received multiple ART lines, including all available nucleoside reverse transcriptase inhibitors and PI from 1987 to March 2007. The CD4 lymphocyte count never exceeded 271 cells/μl and the plasma HIV-2-RNA value never fell below the 100 copies/ml detection limit. The CD4 cell count nadir was 13 cells/μl (4%) and the plasma viral load peak was 16 980 copies/ml. He consecutively developed cytomegalovirus retinitis, oesophageal candidiasis, pulmonary mycobacterial infections (tuberculosis, Mycobacterium kansasii), HIV-2 encephalitis, and hypertension, diabetes mellitus, progressive renal failure requiring dialysis from 2003, myocardial stroke, and peripheral neuropathy. In March 2007, when the CD4 cell count was 27 cells/μl (5%) and the viral load was 6517 copies/ml, he was prescribed lamivudine, abacavir, darunavir/ritonavir, based on reverse transcriptase and protease gene sequencing, and raltegravir. The CD4 cell count (%) rose to 248 cells/μl (6%), 420 cells/μl (13%), and 345 cells/μl (10%) at months 1, 3 and 6, respectively. Viral load was 217 copies/ml at month 1 and was undetectable at months 2, 3 and 6. The same ART strategy was applied to a 46-year-old Malian woman diagnosed with HIV-2 infection in 1995. Baseline values were 392 CD4 cells/μl (28%) and 163 900 copies/ml HIV-2 RNA. She had received all available nucleoside reverse transcriptase inhibitors and PI by 2007, but the CD4 cell count never exceeded 120 cells/μl and an undetectable viral load was never achieved. In March 2007, when the CD4 cell count was 24 cells/μl (7%) and the viral load was 8445 copies/ml, ART was switched to abacavir, tenofovir, darunavir/ritonavir, based on reverse transcriptase and protease gene sequencing, and raltegravir. The CD4 cell count was 27 cells/μl (4%) at month 1, 105 cells/μl (7%) at month 3 and 102 cells/μl (7%) at month 6. The viral load was below 100 copies/ml from month 1 and remained undetectable at months 3 and 6. Plasma antiretroviral concentrations, monitored at month 1, were in the range of expected values. The treatment was well tolerated in both patients. The short-term immunological and virological efficacy of an INI-containing regimen in these two heavily pretreated HIV-2-infected patients is promising. As a result of the few number of active antiretroviral agents available for the treatment of HIV-2-infected patients, this new class of antiretroviral drugs might represent a new therapeutic option to be discussed in combination with drugs selected by reverse transcriptase and protease sequencing and tolerance data, in the setting of the failure of a classic regimen. Nevertheless, this strategy remains to be evaluated for its long-term effects, at best through a multicentre trial.