As of 2007, it was estimated that the rapid scale-up of antiretroviral therapy (ART) in West and Central Africa had resulted in 430 000 patients with advanced HIV disease receiving treatment of a total in need of 1.7 million . Although the prevalence seems to be declining [2–4], West Africa remains the epicentre of the HIV-2 epidemic. Compared to HIV-1, HIV-2 infection is characterized by a longer latency period  and a slower T lymphocyte CD4+ (CD4) depletion with a lower plasma viral load [6,7], but nonetheless leads to clinical AIDS in some instances [8,9]. Unfortunately data on the ART response in HIV-2 and dually positive patients are sparse [10–19]. There is clear evidence that non-nucleoside reverse transcriptase inhibitors (NNRTIs) are inappropriate for the treatment of HIV-2 infection . However, this type of regimen remains the first-line treatment of choice in resource-limited countries . Even when a protease inhibitor regimen has been used results have not always been encouraging [12,14], perhaps due to HIV-2 having a decreased susceptibility to several especially unboosted protease inhibitors , or to the presence of viral resistance mutations prior to the onset of an effective protease inhibitor-based therapy [13,15,22–25]. In Abidjan, a lower CD4 response at 6 months has been reported in HIV-2 and dually positive patients compared to HIV-1-infected patients .
In this context of a rapid scale-up of ART delivery, a consortium of leading clinicians and clinical epidemiologists from five major cities around West Africa, representing 11 adult clinic cohorts has been assembled in West Africa in the context of the global International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration of the US National Institutes of Health [27,28]. Using this international database, we describe the case management of HIV-2-infected or dually positive patients and their response to treatment compared to HIV-1-infected patients in West Africa.
The IeDEA  in West Africa is a prospective, observational multicohort collaboration, established since 2006, assembling data from 11 cohorts of HIV-infected adult patients in Benin , Gambia , Côte d'Ivoire , Mali  and Senegal [31,32]. For the present study, we selected all patients aged 16 or older at ART initiation with a documented date of starting ART, HIV type, and at least one measure of CD4 cell count during the first year of follow-up . For the main analysis comparing NNRTI and protease inhibitor-containing regimens, patients treated by triple nucleoside combinations and other regimens were considered in a third category. The IeDEA West Africa collaboration protocol was approved by the national ethics committees of each country and each clinical site has Federal Wide Assurance (FWA) number identification.
In Côte d'Ivoire, the standard serologic testing algorithm for primary care centres consists in a series of two rapid HIV assays, the Determine HIV-1/HIV-2 (Abbott Diagnostics, Abbott Park, Illinois, USA), followed by the Genie II HIV-1/HIV-2 (Bio-Rad Laboratories, Marne-La-Coquette, France) . The first test used for screening was the same in all countries but in Gambia where the Murex test was used (Abbott Laboratories). The second test was ImmunoComb II HIV 1 & 2 BiSpot (Orgenics Ltd, Israel) for Mali and Senegal, Hexagon HIV (Human, Wiesbaden, Germany) in Gambia. A third test based on Genie II in Mali, ImmunoComb II in Benin or Pepti-lav 1–2 assay (Bio-Rad) in Gambia could be performed in case of discrepancy between the first two test results.
The date of initiation of ART was considered as baseline. Analyses were performed on intent-to-treat basis. The change of CD4 absolute cell count after treatment initiation was analysed using piecewise linear mixed models that take into account correlation of measurements within each patient. The dynamics of CD4 response was modelled with two slopes: before and after 3 months. This change was estimated using a profile likelihood and was in agreement with previously published results [14,35]. The effect of any covariate on each average slope was assessed using a Wald test. Robustness of the results was checked after square root transformation of the CD4 . Loss to follow-up was assumed in patients who were not known to have died and who were not seen for at least 1 year before closing the database for the present analysis. Potential bias due to informative drop-out was checked by comparing these estimates with those from a joint model of longitudinal measurements of CD4 and log time to drop-out . As results were very robust, we are not reporting this latter analysis (available from the authors).
Study population characteristics
Among 17 291 patients, including 16% lost to follow-up (LTFU), 10 073 were eligible for this analysis, including 6% LTFU (Fig. 1). Excluded patients (N = 7218) presented similar baseline characteristics (sex, age, CD4, ART regimen and previous exposure to antiretrovirals) compared to included patients. There were similar rates of patients LTFU in included and excluded patients according to HIV type (P = 0.26). In the present sample, 9482 patients were infected by HIV-1 only, 270 by HIV-2 only and 321 by both types of virus (dually positive patients). Patient characteristics according to the type of infection are reported in Table 1. Patients started combined ART between 1997 and 2007 (85% between 2004 and 2007). More than three-quarters (N = 7894, 78%) of the patients were treated by a NNRTI-based regimen. The most common combinations were stavudine (d4T) + lamivudine (3TC) + nevirapine (29%), d4T + 3TC + efavirenz (22%) and zidovudine (ZDV) + 3TC + efavirenz (19%). Among protease inhibitor-containing regimens (N = 1616), the most common combinations were ZDV + 3TC + indinavir (22%), d4T + 3TC + indinavir (15%) and ZDV + 3TC + nelfinavir (11%). Few patients (N = 470) were treated with a ritonavir-boosted regimen. The remaining other regimens (N = 563) included ZDV + 3TC + abacavir (43%) and d4T + 3TC + didanosine (8%). There were 544 (5.4%) patients who switched a major drug of their regimen (protease inhibitor, NNRTI or abacavir) during the first 12 months. The median time to switch was 4 months [interquartile range (IQR) 2; 8]. Among patients treated with an NNRTI-containing regimen, more HIV-2 and dually positive patients changed to a protease inhibitor-containing regimen compared to HIV-1 patients (P < 0.001). A total of 322 patients switched for a protease inhibitor-containing regimen: 299 were HIV-1-infected patients (4% of those treated with NNRTI), nine were HIV-2-infected patients (20% of those treated with NNRTI) and 14 were dually positive patients (10% of those treated with NNRTI). The time of changing since ART initiation was not significantly different according to the HIV-type (3, 4 and 5 months, respectively, for HIV-1, HIV-2 and dually positive patients).
CD4 response to treatment
The observed baseline median CD4 cell counts were comparable in the three groups: 155 cells/μl in HIV-1, 148 in HIV-2 and 152 in dually positive patients (P = 0.52; Table 1). The estimated baseline values according to the model were also not significantly different by type of infection (P = 0.23). The good agreement between observed and predicted CD4 cell counts over time is illustrated in Fig. 2. The slight overestimation of predicted baseline values was mostly related to missing observations at baseline.
In patients treated with a NNRTI-containing regimen, the CD4 response was weaker in HIV-2 and dually positive patients compared to HIV-1-infected patients (Table 2, Fig. 3). Although identical in the first 3 months on treatment (P = 0.62), the CD4 response was gradually blunted beyond this time point (P = 0.01) for HIV-2-infected patients [−41 cells/μl per year, confidence interval (CI) −123; 40] and dually positive patients (+12 cells/μl per year, CI −34; 58) compared to HIV-1-infected patients (+69 cells/μl per year, CI 63; 75). This led to a significantly lower CD4 cell count 12 months after ART initiation in HIV-2 (268 cells/μl, CI 175; 293) and dually positive patients (277 cells/μl, CI 252; 317) compared to HIV-1 patients (321 cells/μl, CI 319; 328) (P < .001). Of note, the CD4 response beyond the first 3 months on treatment was significantly better in dually positive patients compared to those infected by HIV-2 only (P = 0.03). These results were highly consistent when adjusted for potential confounding factors (sex, age, clinical stage and previous exposure to antiretrovirals). Thus, the estimated CD4 slopes after 3 months for female patients older than 40 years, starting ART at CDC C stage (or WHO stage 3/4) and having never been exposed to antiretrovirals were +72, −30 and +14 cells/μl per year in HIV-1, HIV-2 and dually positive patients, respectively (P = 0.03).
In patients treated by a protease inhibitor-containing regimen, the CD4 response did not differ significantly for the three HIV groups before (P = 0.73) and after 3 months (P = 0.37) (Table 2, Fig. 3). The estimated CD4 cell counts at 12 months was thus similar in HIV-2 (278 cells/μl, CI 248; 307, P = 0.22) and dually positive (271 cells/μl, CI 238; 303, P = 0.25) patients compared to HIV-1-infected patients (303 cells/μl, CI 292; 315). There were no significant differences of HIV type effect on CD4 response after 3 months between boosted and unboosted protease inhibitor-based regimens (all P values >0.35).
In patients treated by another regimen neither containing a NNRTI nor a protease inhibitor, the CD4 response was similar whatever the type of infection (P = 0.49 and P = 0.72, before and after 3 months). The results were similar even after adjustment for the potential confounding factors: age, sex, clinical stage at ART initiation and previous exposure to antiretrovirals (data not shown).
In all analyses, the CD4 responses varied substantially between individuals of the same group of treatment (variance of the individual slopes significantly different from 0, all P values <0.01). This variation was less pronounced in the group of patients treated with an NNRTI-containing regimen, irrespective of the HIV type. In all groups of treatment, the results were consistent after adjusting for centres (data not shown).
In this international collaboration of cohorts of HIV-infected adults including the largest sample of HIV-2 and dually positive patients treated by antiretroviral drugs ever reported, we found that as expected the CD4 response was poor if the patient harboured HIV-2 and was treated with a NNRTI-containing regimen, although it was better in dually positive compared to HIV-2-only infected patients; the efficacy of protease inhibitor-containing regimens was comparable in HIV-1, HIV-2 and dually positive patients, in line for HIV-1 with other published reported [19,26,32,38,39].
There are several explanations for the use of NNRTI-based regimens in these HIV-2 and dually positive patients. First, the information on the HIV type was not always available at the time of treatment initiation. Occasionally, this information only became available after ART initiation and in the context of clinical progression. Second, in some participating clinical centres, NNRTI-containing regimens were the only treatment options available at a given time. This feature is mostly related to the challenging issue of the choice of second-line therapies in resource-limited settings . Thirdly, an efavirenz regimen may have been prescribed in order to avoid protease inhibitor–rifampin interactions during TB-HIV co-treatment (although not recommended in HIV-2 infection). Finally, it is possible that some physicians did not know that NNRTIs are ineffective in HIV-2 infection. The individual justification of this therapeutic choice was not available in this dataset of routinely collected data. Overall, this underlines the need of country-specific medical education in the context of rapid scaling-up as recently advocated [32,41]. If HIV type is not available, although recommended by the WHO guidelines , it would be more appropriate to treat with a protease inhibitor-based regimen or a triple therapy of NRTIs if the CD4 cell count is above 200 cells/μl in HIV-2 endemic countries .
Although protease inhibitor-based regimens did better than those based on NNRTIs, all protease inhibitors did not present the same potency . This underlines the need in studying further the efficacy of specific drugs in the special context of HIV-2 infection. In fact, observational studies like the present one cannot rule out a potential channelling bias. Furthermore, emergence of resistance mutations endorsed the need of increasing antiretroviral treatment potency in HIV-2 patients for the first-line and second-line therapy . We thus believe like others [43,44] that there is a need to conduct new randomized clinical trials to optimize the care of HIV-2-infected patients.
A drawback of this study may be the absence of evaluation of virological response. Such data were not available as these tests are not routinely available. Nevertheless, the immunological response is one of the requested goals of any ART and the one currently recommended by WHO in the public health approach of antiretrovirals . We do not think that the selection for enrolment (based on availability of CD4 and HIV types) or during follow-up (due to withdrawal) could impact our conclusion because there were no strong differences between included and excluded patients according to HIV type, and results were robust according to sensitivity analyses. Another issue is the lack of perfect discrimination between dually positive and HIV-2-infected patients . Hence, the group of dually positive patients could have included a mixture of patients infected by HIV-2 only or both HIV-1 and HIV-2. However, the data from the present observational study come from routine practice and therefore endorse the need for confirmation algorithms of the dual infection by HIV-1 and 2 as well as the cautious use of NNRTI-containing regimens in such circumstances.
In conclusion, the scaling-up of ART in West Africa must fully incorporate the issue of HIV-2-infected patients, in terms of medical training but also for the choice of appropriate medications and diagnostic protocols at clinic and programmatic level. Finally, randomized clinical trials evaluating the new generation of antiretroviral drugs in HIV-2-infected patients are warranted to better defined public health guidelines [3,43,44].
Roles of authors: J.D., R.T., D.K.E and F.D. designed the analysis and wrote the paper. J.D. and R.T. conducted the statistical analysis, S.E. and K.P. contributed to the writing and editing of the manuscript. S.E, M.M., M.D.Z, P.S.S, K.P., E.B. contributed to the design, data and original idea.
We would like to thank Xavier Anglaret for his valuable comments on a previous version of the article.
Composition of the IeDEA-West Africa Collaboration: Primary investigator: Pr François Dabis* (INSERM U897, ISPED, Bordeaux, France).
Co-investigators: Clarisse Amani-Bosse, Franck Olivier Ba-Gomis, Emmanuel Bissagnene*, Man Charurat*, Eric Delaporte, Joseph Drabo*, Serge-Paul Eholie*, Serge-Olivier Koulé, Moussa Maiga*, Eugène Messou, Albert Minga, Kevin Peterson, Papa Salif Sow, Hamar Traoré, Marcel D Zannou*
Others members: Gérard Allou, Xavier Anglaret, Alain Azondékon, Eric Balestre, Jules Bashi, Ye-Diarra, Didier K Ekouévi*, Jean-François Eytard, Antoine Jaquet, Alain Kouakoussui, Valériane Leroy, Charlotte Lewden, Karen Malateste, Lorna Renner, Annie Sasco, Haby Signaté Sy*, Rodolphe Thiébaut, Marguerite Timité-Konan, Hapsatou Touré.
Preliminary results were presented at the 16th conference on Retroviruses and Opportunistic infections, February 8–11, 2009, abstract #600.
Funding: This study was supported by the National Institute of Allergy and Infectious Diseases (NIAID, grant 5U01AI069919-03), together with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Cancer Institute (NCI).
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