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.
1. World Health Organization. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector: progress report 2008
. Geneva: WHO; 2008.
2. van der Loeff MF, Awasana AA, Sarge-Njie R, van der Sande M, Jaye A, Sabally S, et al
. Sixteen years of HIV surveillance in a West African research clinic reveals divergent epidemic trends of HIV-1 and HIV-2. Int J Epidemiol 2006; 35:1322–1328.
3. Eholie S, Anglaret X. Commentary: decline of HIV-2 prevalence in West Africa: good news or bad news? Int J Epidemiol 2006; 35:1329–1330.
4. Valadas E, Franca L, Sousa S, Antunes F. 20 Years of HIV-2 infection in Portugal: trends and changes in epidemiology. Clin Infect Dis 2009; 48:1166–1167.
5. Whittle H, Morris J, Todd J, Corrah T, Sabally S, Bangali J, et al
. HIV-2-infected patients survive longer than HIV-1-infected patients. AIDS 1994; 8:1617–1620.
6. Berry N, Ariyoshi K, Jaffar S, Sabally S, Corrah T, Tedder R, Whittle H. Low peripheral blood viral HIV-2 RNA in individuals with high CD4 percentage differentiates HIV-2 from HIV-1 infection. J Hum Virol 1998; 1:457–468.
7. MacNeil A, Sarr AD, Sankale JL, Meloni ST, Mboup S, Kanki P. Direct evidence of lower viral replication rates in vivo in human immunodeficiency virus type 2 (HIV-2) infection than in HIV-1 infection. J Virol 2007; 81:5325–5330.
8. Martinez Steele E, Awasana AA, Corrah T, Sabally S, van der Sande M, Jaye A, et al
. Is HIV-2-induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic. AIDS 2007; 21:317–324.
9. van der Loeff MFS, Martinez Steele E, Corrah T, Awasana AA, van der Sande M, Sarge Njie R, et al
. HIV-2-induced AIDS different from HIV-1-associated AIDS? AIDS 2008; 22:791–792.
10. Schutten M, van der Ende ME, Osterhaus AD. Antiretroviral therapy in patients with dual infection with human immunodeficiency virus types 1 and 2. N Engl J Med 2000; 342:1758–1760.
11. Witvrouw M, Pannecouque C, Switzer WM, Folks TM, De Clercq E, Heneine W. Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antiviral Ther 2004; 9:57–65.
12. Matheron S, Damond F, Benard A, Taieb A, Campa P, Peytavin G, et al
. CD4 cell recovery in treated HIV-2-infected adults is lower than expected: results from the French ANRS CO5HIV-2 cohort. AIDS 2006; 20:459–462.
13. Jallow S, Kaye S, Alabi A, Aveika A, Sarge Njie R, Sabally S, et al
. Virological and immunological response to Combivir and emergence of drug resistance mutations in a cohort of HIV-2 patients in The Gambia. AIDS 2006; 20:1455–1458.
14. Drylewicz J, Matheron S, Lazaro E, Damond F, Bonnet F, Simon F, et al
. Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients in France. AIDS 2008; 22:457–468.
15. Smith RA, Anderson DJ, Pyrak CL, Preston BD, Gottlieb GS. Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J Infect Dis 2009; 199:1323–1326.
16. Borget MY, Diallo K, Adje-Toure C, Chorba T, Nkengasong JN. Virologic and immunologic responses to antiretroviral therapy among HIV-1 and HIV-2 dually infected patients: case reports from Abidjan, Cote d'Ivoire. J Clin Virol 2009; 45:72–75.
17. Benard A, Damond F, Campa P, Peytavin G, Descamps D, Lascoux-Combes C, et al
. Good response to lopinavir/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients. AIDS 2009; 23:1171–1173.
18. Sarfo FS, Bibby DF, Schwab U, Appiah LT, Clark DA, Collini P, et al
. Inadvertent nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in dual HIV-1/2 and HIV-2 seropositive West Africans: a retrospective study. J Antimicrob Chemother 2009; 64:667–669.
19. Jallow S, Alabi A, Sarge-Njie R, Peterson K, Whittle H, Corrah T, et al
. Virological response to highly active antiretroviral therapy in patients infected with human immunodeficiency virus type 2 (HIV-2) and in patients dually infected with HIV-1 and HIV-2 in the Gambia and emergence of drug-resistant variants. J Clin Microbiol 2009; 47:2200–2208.
20. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK. Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to nonnucleoside inhibitors. Proc Natl Acad Sci U S A 2002; 99:14410–14415.
21. Brower ET, Bacha UM, Kawasaki Y, Freire E. Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use. Chem Biol Drug Design 2008; 71:298–305.
22. Descamps D, Damond F, Matheron S, Collin G, Campa P, Delarue S, et al
. High frequency of selection of K65R and Q151 M mutations in HIV-2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen. J Med Virol 2004; 74:197–201.
23. Gottlieb GS, Badiane NMD, Hawes SE, Fortes L, Toure M, Ndour CT, et al
. Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resource-limited West Africa. Clin Infect Dis 2009; 48:476–483.
24. Landman R, Damond F, Gerbe J, Brun Vezinet F, Yeni P, Matheron S. Immunovirological and therapeutic follow-up of HIV-1/HIV-2-dually seropositive patients. AIDS 2009; 23:426–428.
25. Jallow S, Vincent T, Leligdowicz A, De Silva T, Van Tienen C, Alabi A, et al
. Presence of a multidrug-resistance mutation in an HIV-2 variant infecting a treatment-naive individual in Caio, Guinea Bissau. Clin Infect Dis 2009; 48:1790–1793.
26. Toure S, Kouadio B, Seyler C, Traore M, Dakoury Dogbo N, Duvignac J, et al
. Rapid scaling-up of antiretroviral therapy in 10000 adults in Cote d'Ivoire: 2-year outcomes and determinants. AIDS 2008; 22:873–882.
28. Brinkhof MW, Boulle A, Weigel R, Messou E, Mathers C, Orrell C, et al
. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. Plos Med 2009; 6:e1000066.
29. Hounton SH, Akonde A, Zannou DM, Bashi J, Meda N, Newlands D. Costing universal access of highly active antiretroviral therapy in Benin. AIDS Care 2008; 20:582–587.
30. Boileau C, Nguyen VK, Sylla M, Machouf N, Chamberland A, Traore HA, et al
. Low prevalence of detectable HIV plasma viremia in patients treated with antiretroviral therapy in Burkina Faso and Mali. J Acquir Immune Defic Syndr 2008; 48:476–484.
31. Etard JF, Ndiaye I, Thierry-Mieg M, Gueye NF, Gueye PM, Laniece I, et al
. Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study. AIDS 2006; 20:1181–1189.
32. Sow PS, Otieno LF, Bissagnene E, Kityo C, Bennink R, Clevenbergh P, et al
. Implementation of an antiretroviral access program for HIV-1-infected individuals in resource-limited settings: clinical results from 4 African countries. J Acquir Immune Defic Syndr 2007; 44:262–267.
33. Thiébaut R, Walker S. When it is better to estimate a slope with only one point. QJM Quater J Med 2008; 101:821–824.
34. Rouet F, Ekouevi DK, Inwoley A, Chaix ML, Burgard M, Bequet L, et al
. Field evaluation of a rapid human immunodeficiency virus (HIV) serial serologic testing algorithm for diagnosis and differentiation of HIV type 1 (HIV-1), HIV-2, and dual HIV-1-HIV-2 infections in West African pregnant women. J Clin Microbiol 2004; 42:4147–4153.
35. Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, et al
. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nature Med 1998; 4:208–214.
36. Jacqmin Gadda H, Sibillot S, Proust C, Molina JM, Thiébaut R. Robustness of the linear mixed model to misspecified error distribution. Computat Stat Data Anal 2007; 51:5142–5154.
37. Thiébaut R, Jacqmin-Gadda H, Babiker A, Commenges D. Joint modelling of bivariate longitudinal data with informative dropout and left-censoring, with application to the evolution of CD4+cell count and HIV RNA viral load in response to treatment of HIV infection. Stat Med 2005; 24:65–82.
38. Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, Chi BH, et al
. Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 2006; 296:782–793.
39. Nash D, Katyal M, Brinkhof MW, Keiser O, May M, Hughes R, et al
. Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies. AIDS 2008; 22:2291–2302.
40. Pujades-Rodriguez M, O'Brien D, Humblet P, Calmy A. Second-line antiretroviral therapy in resource-limited settings: the experience of Medecins Sans Frontieres. AIDS 2008; 22:1305–1312.
41. Souville M, Msellati P, Carrieri MP, Brou H, Tape G, Dakoury G, Vidal L. Physicians' knowledge and attitudes toward HIV care in the context of the UNAIDS/Ministry of Health Drug Access Initiative in Cote d'Ivoire. AIDS 2003; 17(Suppl 3):S79–S86.
42. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach:–2006 revision
. Geneva: WHO; 2006.
43. Gottlieb GS, Eholie SP, Nkengasong JN, Jallow S, Rowland-Jones S, Whittle HC, Sow PS. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS 2008; 22:2069–2072.
44. Matheron S. HIV-2 infection: a call for controlled trials. AIDS 2008; 22:2073–2074.