HIV-2 infection: a call for controlled trials

The paper by Gottlieb et al.[1] recalls the particularities of HIV-2 infection and calls for dedicated randomized controlled trials of antiretroviral therapy in West Africa. Randomized trials are indeed the only way of determining most effective antiretroviral combination(s) for both antiretroviral-naive and antiretroviral-experienced patients. Many HIV-2-infected patients live in parts of western Europe with historical ties to West Africa, especially France and Portugal. However, their numbers are insufficient for conclusive randomized trials. The ACHIeV2E network of clinicians, virologists, immunologists, epidemiologists and statisticians belonging to research centers located in 10 countries in Europe and two in West Africa was created to conduct such trials and thus to establish international guidelines for the treatment and management of HIV-2-infected patients. The design, inclusion criteria, endpoints for efficacy and statistical methods of trials designed to define the optimal treatment for HIV-2 infection should theoretically be the same as those used for HIV-1, in terms of methodological rigor and statistical power. But certain particularities of HIV-2 infection must be taken into account when designing such studies, and the first step is to identify the prerequisites and constraints resulting from this requirement. The main issues concern the target population, the best candidate drugs and combinations, and the therapeutic strategies that warrant testing. Another question is whether the endpoints and statistical methods used to analyze the response to treatment for HIV-1 infection are also appropriate for HIV-2 infection. The inclusion criteria should be based on the degree of immunodeficiency and the viral load value at which therapy can be expected to be optimally beneficial. The poor immunological response to treatment observed in several retrospective studies of HIV-2 infection could be due to the lesser viral potency of the antiretrovirals used, the relatively low replicative capacity of HIV-2 and/or excessively late intervention in the course of the disease. This latter possibility is supported by a comparative study of the immunovirological response to highly active antiretroviral therapy (HAART) in matched HIV-1-infected and HIV-2-infected patients, based on factors associated with HIV-1 disease progression. The results showed smaller initial and subsequent CD4 cell count increments and weaker virological responses in HIV-2-infected patients. However, it is noteworthy that all the patients started treatment at the CD4 cell count threshold used for HIV-1 infection, which is reached later in the course of HIV-2 disease [2]. These data therefore support earlier antiretroviral treatment of HIV-2-infected patients. The most appropriate CD4 cell count threshold for study entry must first be agreed on or determined in specific studies. The choice of a plasma HIV-2 RNA level above the current detection limit of 100 copies/ml as an inclusion criterion would exclude many patients, as fewer HIV-2-infected patients than HIV-1-infected patients have detectable viral load. For example, the proportion of patients with detectable viral load at enrolment in the French ANRS HIV-2 cohort is only 29% overall, ranging from 8% in patients with CD4 cell count > 500 cells/μl to 35% in those with CD4 cell count between 300 and 500 cells/μl and 62% in those with CD4 cell count < 300 cells/μl. The median viral load is only 2.09 log10 copies/ml. The choice of drugs, combinations and/or strategies for these trials is also controversial. Currently, a combination of two nucleoside reverse transcriptase inhibitors (NRTI) and a boosted protease inhibitor is the standard regimen. More recent protease inhibitors than those used in published reports might induce better immune reconstitution, and phenotypic studies of darunavir have given promising results. Integrase inhibitors have also proven effective in vitro, and case reports mentioned very good immunovirological responses to a combination of boosted darunavir and genotype-selected NRTI in three patients with multiple treatment failure. The effectiveness of CCR5 co-receptor blockers remains to be determined in vitro, and phenotypic or genotypic tests of HIV-2 tropism will need to be improved before these agents can be included in the antiretroviral combinations used for these trials. The optimal therapeutic strategy is another unknown, including the possible advantages of induction–maintenance regimens. One common endpoint in trials of treatments for HIV-1 infection is viral load undetectability. In contrast, plasma HIV-2 RNA load cannot be used as the sole primary endpoint for HIV-2-infected patients for the reasons stated above. Furthermore, in the absence of a commercial assay, a variety of methods are used to measure HIV-2 RNA in plasma and their results are somewhat divergent. Standardization of plasma HIV-2 RNA quantification is thus a prerequisite for therapeutic trials of antiretroviral combinations [3]. Considering the low replication of HIV-2, the use of sophisticated statistical methods to analyze the response to treatment, including the expected gain in CD4 cells, might enable the enrolment of all HIV-2-infected patients qualifying for treatment, whatever their viral load may be. The main focus of these trials could be either the point at which treatment should be started or the optimal therapeutic combination or strategy, depending on the main mechanisms considered underlying the generally weak immunological response to therapy. These trials should include, if possible, genotypic and phenotypic investigations of virological failures aimed at identifying resistance mutations and pathway and at developing algorithms for the selection of initial and subsequent lines of therapy. These trials should be reserved for HIV-2-monoinfected patients, as virological differentiation between dual HIV-1 and HIV-2 infection and dual seropositivity is difficult and not routinely available everywhere. The results of trials of antiretroviral combinations in patients with isolated HIV-2 infection will also be useful to define guidelines for dually infected patients. International collaboration between West African and European research centers would be the best way to settle these questions, and is required in order to design and conduct the randomized trials needed for evidenced-based treatment of HIV-2-infected patients, wherever they live.