In high-income countries, the availability of highly active antiretroviral therapy (HAART) has led to major reductions in morbidity and mortality from HIV infection.1-3 Several studies in this setting have demonstrated a stronger correlation between long-term prognosis and virologic response (VR) and immunologic response (IR) after 6 months on HAART than with baseline values.4-6 In general, the initiation of HAART leads to a significant reduction in HIV plasma viral load (PVL) and an increase in CD4 cell count.7,8 Some patients on HAART exhibit a pattern of sustained CD4 cell response despite persistent viremia or do not exhibit a significant rise in CD4 cell count despite viral suppression, however. Both situations are referred to as discordant responses and have been consistently associated with an intermediate risk of developing an AIDS event or death in developed countries.9-12
In high-income countries, discordant responses have been reported to occur in 20% to 30% of patients 6 months to 2 years after starting HAART.4,9,13-16 In developing countries, the effectiveness of HAART in suppressing viral replication and inducing a rise in CD4 cell counts is comparable to what has been reported from developed countries.17-22 Nonetheless, to date, there is scant information on the frequency and prognostic significance of discordant responses to HAART in low-income countries, where patients often start therapy at advanced stages of immune deficiency and frequently have comorbidities that may impair their response to therapy.23
We report on the frequency of and risk factors for discordant responses at 6 months on HAART in previously treatment-naive HIV patients in resource-limited countries.
Patients and Measurements
The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration is a network of HIV treatment programs in Africa, Latin America, and Asia. The ART-LINC Collaboration has been described previously.24,25 The selection of patients and data extraction were done at the participating sites. Data were anonymized locally and then pooled and analyzed centrally. At all sites, local ethics committees or institutional review boards approved the collection of data.
Only sites that collected HIV PVLs routinely were included in the analysis. All previously treatment-naive individuals who initiated therapy between March 1996 and April 2004, had a known date of therapy initiation, were aged 16 years or older, and had a documented CD4 cell count at baseline were included in this analysis.
The type of HAART regimen was defined as protease inhibitor (PI) based (1 PI + 2 nucleoside reverse transcriptase inhibitors [NRTIs], including ritonavir-boosted regimens), nonnucleoside reverse transcriptase (NNRTI) based (1 NNRTI + two NRTIs), or a nonstandard HAART regimen (including triple-NRTI regimens and any other regimen containing a minimum of 3 drugs). The stage of disease was classified as less (Centers for Disease Control and Prevention [CDC] stage A/B, World Health Organization [WHO] stage I or II) or more advanced (CDC stage C, WHO stage III or IV). The baseline CD4 cell count and HIV PVL were measured at therapy initiation (−180 or 7 days).
Study Outcomes and Statistical Analysis
VR was defined as achieving a plasma HIV PVL <500 copies/mL, whereas IR was defined as an increase of at least 50 CD4 cells/μL at 6 months. Measurements closest to 6 months after starting HAART, within 3 to 9 months, were used in these analyses. Outcomes were defined as complete response (VR+IR+), virologic-only response (VR+IR−), immunologic-only response (VR−IR+), and nonresponse (VR−IR−). An intent-to-continue-treatment approach, which ignored subsequent therapy changes or interruptions, was used. Between-group comparisons were made by using the χ2 test for categoric variables and the Kruskall-Wallis test for continuous variables. A multinomial logistic regression model was fit to assess the relation between baseline characteristics and the 6-month outcomes. Heterogeneity introduced by different sites was accounted for by including site as a fixed effect in the model, and Huber-White robust SEs were calculated to account for intrasite correlation.
Missing baseline information on stage of disease and PVL were multiply imputed, based on whether the patient died, site, CD4 cell count, gender, age, and type of HAART regimen. In these imputations, values of the missing data were randomly sampled from their predicted distributions. Analyses were run on each of 20 data sets that included the imputed values, and the results were combined with the rules of Rubin.26 Analyses were performed using STATA version 9.0 (Stata Corporation, College Station, TX).
During the study period, 4810 patients initiated HAART. Of these, 158 (3.2%) died within 6 months of therapy and 1541 (32.0%) were from sites where the viral load was not routinely measured, and thus were not included in the analysis. The demographic and clinical characteristics of the remaining 3111 patients are shown in Table 1 according to IRs and VRs at 6 months on therapy. Approximately half were male (50.9%), with a median age at HAART initiation of 35 years. The median baseline CD4 cell count and HIV RNA PVL were 137 (interquartile range [IQR]: 49-240) cells/μL and 5.1 (IQR: 4.6-5.6) log10 copies/mL, respectively; 1591 (51.1%) had more advanced disease, and 1783 (57.3%) were prescribed an NNRTI-based regimen. Excluded patients were more likely to be female (55% vs. 45%; P < 0.01) and to have a lower baseline CD4 cell count (70 vs. 136 cells/μL; P < 0.01).
Most patients (57.3%) started therapy with an NNRTI-based regimen, and 29% started with a PI-based regimen. The most frequently prescribed NNRTIs and PIs were efavirenz (66.1%) and indinavir (48.8%), respectively. PI-based regimens were more commonly prescribed before 2000 (64.0%). From 2000 onward, NNRTI-based regimens predominated (76.0%).
Recipients of nonstandard HAART regimens had the highest median baseline CD4 count (185 [IQR: 63-315] cells/μL), whereas recipients of PI-based and NNRTI-based regimens had similar median baseline counts (131 [IQR: 45-253] cells/μL and 131 [IQR: 48-222] cells/μL, respectively). The baseline PVLs for recipients of NNRTI-based, PI-based, and nonstandard regimens were 5.1 (IQR: 4.6-5.6) log10 copies/mL, 5.2 (IQR: 4.7-5.7) log10 copies/mL, and 4.9 (IQR: 4.5-5.5) log10 copies/mL, respectively (data not shown).
Immunologic and Virologic Responses at 6 Months of Therapy
At 6 months on therapy, 1914 (61.5%) patients had information on PVLs and CD4 cell counts. For 1197 (38.5%), the outcome could not be ascertained because of missing data on PVLs or CD4 cell counts. Among these patients, 292 (24.4%) were lost to follow-up at 6 months.
Among the patients with available information, 1074 (56.1%) were complete responders, 364 (19.0%) were virologic-only responders, 283 (14.8%) were immunologic-only responders, and 193 (10.1%) were nonresponders (Table 2). The overall VR rate was 75.1%, the median increase in CD4 count was 106 (IQR: 40-178) cells/μL, and the median viral load reduction was 2.8 (IQR: −3.4 to −1.9) log10 copies/mL. Complete responders showed the greatest CD4 cell count increases and PVL decreases, and nonresponders showed the smallest changes in these measurements.
Table 3 shows the results of the multinomial logistic regression model for 1914 patients with a known response, with complete responders as the reference group, controlling for demographic and clinical variables, calendar year, and participating site. There were no significant differences by gender between complete responders and all other categories of response.
In comparison to complete responders, virologic-only responders were significantly more likely to be older than 50 years of age, to have a baseline CD4 count >99 cells/μL, or to have received nonstandard HAART regimens and were less likely to have a baseline HIV RNA PVL >100,000 copies/mL (see Table 3).
Patients who showed an immunologic-only response were less likely than complete responders to be older than 30 years of age and to have a baseline CD4 count >99 cells/μL and were more likely to have a baseline HIV RNA PVL >100,000 copies/mL or to have received a PI-based regimen (see Table 3). The probability of having an immunologic-only or nonresponse rather than a complete response decreased after 2000 (data not shown).
Some covariates had opposite effects on the 2 categories of discordant responses. Increasing age, increasing baseline CD4 cell count, and other regimens were positively associated with virologic-only responses, and PI-based regimens were positively associated with immunologic-only responses, whereas a baseline HIV RNA PVL ≥100,000 copies/mL was negatively associated with virologic-only responses and positively associated with immunologic-only responses. Figure 1 shows the adjusted odds ratios of discordant responses by baseline CD4 cell count strata, with complete responders as the reference group.
We assessed the extent to which the rate of unknown response could have introduced bias in our analysis by comparing baseline characteristics and VRs and IRs between patients with known and unknown responses at 6 months. Patients with known and unknown responses at 6 months did not differ with respect to gender, age, or baseline CD4 cell count (see Table 1). Patients with unknown responses were more likely to have received an NNRTI-based regimen and to have an unknown baseline PVL and stage of disease. At 6 months of therapy, however, patients with an unknown response who had available information on VR or IR (but not both) had overall similar median changes in CD4 cell counts and PVLs as patients with both responses known (112 vs. 105 cells/μL, P = 0.26; and −2.7 vs. −2.8 log10 copies/mL, P = 0.88, respectively). A multinomial model that included a missing outcome category led to similar results, supporting the hypothesis that this subgroup of patients did not significantly differ from the 1914 patients with known outcomes.
To our knowledge, this is the first report on the frequency of and risk factors for discordant responses in a large cohort of patients initiating HAART in low-income countries. The encountered frequency of a discordant response (33.8%) at 6 months of therapy is similar to what has been reported from high-income countries.10,11,14-16 We have found that compared with complete responders, virologic-only responders were older, had higher baseline CD4 cell counts, had lower baseline PVLs, and were more likely to have received a nonstandard HAART regimen and that immunologic-only responders were younger, had lower baseline CD4 cell counts, and were more likely to have received a PI-based or nonstandard regimen.
Our finding of older age being associated with a virologic-only response and inversely associated with an immunologic-only response is consistent with studies conducted in high-income countries10-12,27 and the hypothesis that the magnitude of immune restoration is dependent on thymic activity, which decreases with age.28 Other reports from high-income countries have also demonstrated that older age is independently associated with impaired IRs despite sustained VRs.29 It is also suggestive of better adherence among older patients, in agreement with other studies.30,31
As in reports from high-income countries, a higher baseline CD4 cell count was associated with an increased probability of a virologic-only response and with a reduced probability of an immunologic-only response.10,11,32 One possible explanation for this finding is the nonlinear nature of CD4 cell count increases after HAART initiation across the different baseline CD4 count strata. In agreement with the findings of Moore et al,11 our results also suggest that increases in CD4 counts after initiation of therapy might be greater in individuals with lower CD4 cell counts at therapy initiation. A baseline PVL greater than 100,000 copies/mL was associated with a lower probability of having a virologic-only response, a finding also reported in the studies of Moore et al11 and Nicastri et al.10
Our analysis showed that immunologic-only responders were 1.6 times more likely than complete responders to have received PI-based regimens rather than NNRTI-based regimens. This finding has to be interpreted with caution, however. As noted previously, differences in response between HAART regimens in this observational study are likely to be subject to selection by indication bias. Nonetheless, it has been suggested that the additional effect of PIs on the IR could be attributable to their ability to reduce T-cell apoptosis.13 A superior IR to PIs compared with NNRTIs was suggested among virologic responders33 but not among patients showing a discordant response.11,27,34 This issue is unlikely to be fully elucidated by observational studies.
Qualitative differences in the effects of predictors of the 2 types of discordant responses support the hypothesis of different underlying mechanisms. Although the long-term clinical outcomes seem to be comparable,11 identifying risk factors for both types of early discordant response may lead to specific preventive strategies for each type.
Discordant responses have been associated with increased risk of clinical progression and mortality in developed countries. In a cohort of antiretroviral-experienced patients with advanced HIV disease who started PI-based HAART and were followed for longer than 30 months, discordant responders at 12 months experienced significantly more AIDS-defining events than full responders, with immunologic-only responders having a slightly higher probability of being event-free compared with virologic-only responders.27 In another study involving more than 2100 antiretroviral-experienced and -naive HIV patients followed for a median of 44 months, immunologic-only and virologic-only responders had a significantly lower risk of clinical progression than nonresponders but 2.3- and 1.9-fold greater risks of death or new AIDS-defining events than complete responders, respectively.10
Little is known about the mechanisms underlying the development of discordant responses, but they are apparently dependent on the interaction of a multitude of viral and host factors. One hypothesis is that HAART selects viral strains that are less fit, which, in turn, results in reduced pathogenicity of drug-resistant viruses. In fact, it has been shown that recipients of PI-based regimens with prolonged discordance (immunologic success despite virologic failure) have decreased viral replication capacity.35-37 In a closely followed cohort of HAART-naive patients for whom repeated measures over a period of 1 year were analyzed, almost all patients who showed a discordant IR at 1 year had had a prior transient period of undetectable PVL or partial suppression of PVL to <1000 copies/mL, suggesting that partial viral suppression is the primary mechanism involved in discordant CD4 cell count increases.29 Genetic variability, such as polymorphisms associated with drug transportation38 and T-lymphocyte apoptosis,39,40 has been implicated in the pathogenesis of the virologic-only response. In addition, the concomitant use of tenofovir and didanosine has been shown to cause an impaired IR.41,42 In the ART-LINC Collaboration, the negligible proportion of patients initiating therapy with this combination is not likely to have influenced our results.
A major strength of the present study is the large number of previously antiretroviral-naive patients starting therapy with NNRTI-based regimens. Most studies published so far have been conducted in developed countries and have included experienced patients receiving PI-based regimens; these patients are not representative of patients starting therapy in resource-limited settings, where most start treatment with NNRTI-based regimens.24,25
Our study has several limitations. First, this study did not address the impact of adherence on outcomes. In the study of Moore et al,11 suboptimal adherence was predictive of virologic-only and immunologic-only responses rather than complete response. Second, additional variability may have been introduced as a result of differences in population genetics or infecting HIV subtypes, which were not considered in the present analysis. Third, patients prescribed NNRTIs had lower plasma HIV RNA levels and higher CD4 cell counts than patients prescribed PIs, highlighting the importance of provider bias in determining differences between different regimens.43 Fourth, we acknowledge that the 38% unknown response rate could potentially affect our results. Our analysis showed that this group of patients did not differ significantly from the patients in the other categories of response with respect to major baseline risk factors, however. We believe that the availability of laboratory resources on-site or other factors that limited access to laboratory tests were determinants of this response pattern rather than patient characteristics. In addition, including patients with an unknown response at 6 months did not substantially change the estimates in the final model. Finally, if the limited availability of resources caused programs to prioritize monitoring VRs and IRs in patients who did not seem to be doing well clinically, we could have underestimated the virologic and immunologic effectiveness of HAART in these settings.
Our results add to accumulating data on response to therapy in resource-limited countries and may have important public health implications. We showed that despite considerable differences in disease severity at presentation and baseline CD4 cell counts of patients in resource-limited settings, the frequency of and risk factors for discordant response are similar to those observed in developed countries. In these countries, higher mortality has increasingly been reported for discordant responders than for complete responders. Clinical management of these patients often requires a more sophisticated laboratory approach (genotypic and phenotypic resistance) and the availability of second-line therapy. Data on the frequency of this phenomenon and identification of its risk factors are of prime importance and may help HIV/AIDS programs to plan their laboratory and therapeutic resources. Further studies are needed to assess the long-term impact of early discordant responses in these resource-limited countries.
The authors are grateful to Jack Whitescarver, Michel Kazatchkine, and Brigitte Bazin for their encouragement and support. The authors also thank all the patients and collaborating center staff who made this project possible as well as Margaret May, Jonathan Sterne, Lotti Senn, Raffaele Battaglia, Gian Tony, and Sophie Lamarque for ongoing help and advice.
1. Hogg RS, Heath KV, Yip B, et al. Improved survival among HIV-infected individuals following initiation of antiretroviral therapy
2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med
3. Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. Swiss HIV Cohort Study. BMJ
4. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy
: a collaborative analysis of prospective studies. Lancet
5. Grabar S, Le Moing V, Goujard C, et al. Response to highly active antiretroviral therapy
at 6 months and long-term disease progression in HIV-1 infection. J Acquir Immune Defic Syndr
6. Anastos K, Barron Y, Cohen MH, et al. The prognostic importance of changes in CD4+ cell count and HIV-1 RNA level in women after initiating highly active antiretroviral therapy
. Ann Intern Med
7. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy
. N Engl J Med
8. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy
in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet
9. Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy
. Ann Intern Med
10. Nicastri E, Chiesi A, Angeletti C, et al. Clinical outcome after 4 years follow-up of HIV-seropositive subjects with incomplete virologic or immunologic response to HAART. J Med Virol
11. Moore DM, Hogg RS, Yip P, et al. Discordant
immunologic and virologic responses to highly active antiretroviral therapy
are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr
12. Marimoutou C, Chene G, Mercie P, et al. Prognostic factors of combined viral load
cell count responses under triple-antiretroviral therapy
, Aquitaine Cohort, 1996-1998. J Acquir Immune Defic Syndr
13. Deeks SG, Grant RM. Sustained CD4 responses after virological failure of protease inhibitor-containing therapy. Antivir Ther
. 1999;4(Suppl 3):7-11.
14. Piketty C, Castiel P, Belec L, et al. Discrepant responses to triple combination antiretroviral therapy
in advanced HIV disease. AIDS
15. Kaufmann D, Pantaleo G, Sudre P, et al. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy
(HAART). Swiss HIV Cohort Study. Lancet
16. Mehta S, Lucas G, Astemborski J, et al. Discordant
responses to HAART and clinical outcomes among injection drug users in Baltimore, Maryland [abstract 527]. Presented at: Thirteenth Conference on Retroviruses and Opportunistic Infections; 2006; Denver.
17. Tuboi SH, Harrison LH, Sprinz E, et al. Predictors of virologic failure in HIV-1-infected patients starting highly active antiretroviral therapy
in Porto Alegre, Brazil. J Acquir Immune Defic Syndr
18. Zhou J, Kumarasamy N, Ditangco R, et al. The TREAT Asia HIV Observational Database: baseline and retrospective data. J Acquir Immune Defic Syndr
19. Ivers LC, Kendrick D, Doucette K. Efficacy of antiretroviral therapy
programs in resource-poor settings: a meta-analysis of the published literature. Clin Infect Dis
20. Coetzee D, Hildebrand K, Boulle A, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS
21. Landman R, Schiemann R, Thiam S, et al. Once-a-day highly active antiretroviral therapy
in treatment-naive HIV-1-infected adults in Senegal. AIDS
22. Hofer CB, Schechter M, Harrison LH. Effectiveness of antiretroviral therapy
among patients who attend public HIV clinics in Rio de Janeiro, Brazil. J Acquir Immune Defic Syndr
23. Holmes CB, Losina E, Walensky RP, et al. Review of human immunodeficiency virus type 1-related opportunistic infections in sub-Saharan Africa. Clin Infect Dis
24. Braitstein P, Brinkhof MW, Dabis F, et al. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy
: comparison between low-income and high-income countries. Lancet
25. Dabis F, Balestre E, Braitstein P, et al. Cohort profile: Antiretroviral Therapy
in Lower Income Countries (ART-LINC): international collaboration of treatment cohorts. Int J Epidemiol
26. Rubin D. Multiple Imputation for Nonresponse in Surveys
. New York: Wiley; 1987.
27. Piketty C, Weiss L, Thomas F, et al. Long-term clinical outcome of human immunodeficiency virus-infected patients with discordant
immunologic and virologic responses to a protease inhibitor-containing regimen. J Infect Dis
28. Teixeira L, Valdez H, McCune JM, et al. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. AIDS
29. Wood E, Hogg RS, Yip B, et al. “Discordant
” increases in CD4 cell count relative to plasma viral load
in a closely followed cohort of patients initiating antiretroviral therapy
. J Acquir Immune Defic Syndr
30. Glass TR, De Geest S, Weber R, et al. Correlates of self-reported nonadherence to antiretroviral therapy
in HIV-infected patients: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr
31. Hinkin CH, Hardy DJ, Mason KI, et al. Medication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuse. AIDS
. 2004;18(Suppl 1):S19-S25.
32. Spritzler J, Mildvan D, Russo A, et al. Can immune markers predict subsequent discordance between immunologic and virologic responses to antiretroviral therapy
? Adult AIDS Clinical Trials Group. Clin Infect Dis
33. Barreiro P, Soriano V, Casas E, et al. Different degree of immune recovery using antiretroviral regimens with protease inhibitors or non-nucleosides. AIDS
34. Benito JM, Lopez M, Martin JC, et al. Differences in cellular activation and apoptosis in HIV-infected patients receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors. AIDS Res Hum Retroviruses
35. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med
36. Sufka SA, Ferrari G, Gryszowka VE, et al. Prolonged CD4+ cell/virus load discordance during treatment with protease inhibitor-based highly active antiretroviral therapy
: immune response and viral control. J Infect Dis
37. Sarmati L, Montano M, Dori L, et al. Discordant
response to HAART: reduction of viremia and replicative capacity of HIV strains in patients after genotype guided change of therapy. New Microbiol
. 2004;27(Suppl 1):95-98.
38. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet
39. Nasi M, Pinti M, Bugarini R, et al. Genetic polymorphisms of Fas (CD95) and Fas ligand (CD178) influence the rise in CD4+ T cell count after antiretroviral therapy
in drug-naive HIV-positive patients. Immunogenetics
40. Fernandez S, Rosenow AA, James IR, et al. Recovery of CD4+
T cells in HIV patients with a stable virologic response to antiretroviral therapy
is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes. J Acquir Immune Defic Syndr
41. Barrios A, Rendon A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS
42. Karrer U, Ledergerber B, Furrer H, et al. Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir. AIDS
43. Wood E, Hogg RS, Heath KV, et al. Provider bias in the selection of non-nucleoside reverse transcriptase inhibitor and protease inhibitor-based highly active antiretroviral therapy
and HIV treatment outcomes in observational studies. AIDS
Antiretroviral Therapy in Low-Income Countries Collaboration
- Writing Committee: Suely H. Tuboi, Martin Brinkhof, Mathias Egger, Roslyn A. Stone, Paula Braitstein, Denis Nash, Eduardo Sprinz, François Dabis, Lee H. Harrison, and Mauro Schechter
- Principal Investigators: François Dabis, Matthias Egger, and Mauro Schechter
- Central Team: Eric Balestre, Paula Braitstein, Martin Brinkhof, and Catherine Seyler
- Steering Group: Kathy Anastos (Kigali, Rwanda), Franck-Olivier Ba-Gomis (Abidjan, Côte d'Ivoire), David Bangsberg (Mbarara/Kampala, Uganda), Andrew Boulle (Cape Town, South Africa), Jennipher Chisanga (Lusaka, Zambia), Eric Delaporte (Dakar, Senegal), Diana Dickinson (Gaborone, Botswana), Ernest Ekong (Lagos, Nigeria), Kamal Marhoum El Filali (Casablanca, Morocco), Mina Hosseinipour (Lilongwe, Malawi), Charles Kabugo (Kampala, Uganda), Silvester Kimaiyo (Eldoret, Kenya), Mana Khongphatthanayothin (Bangkok, Thailand), N. Kumarasamy (Chennai, India), Christian Laurent (Yaounde, Cameroon), Ruedi Luthy (Harare, Zimbabwe), James McIntyre (Johannesburg, South Africa), Timothy Meade (Lusaka, Zambia), Eugene Messou (Abidjan, Côte d'Ivoire), Denis Nash (New York, NY), Adama Ndir (Dakar, Senegal), Winstone Nyandiko Mokaya (Eldoret, Kenya), Margaret Pascoe (Harare, Zimbabwe), Larry Pepper (Mbarara, Uganda), Papa Salif Sow (Dakar, Senegal), Sam Phiri (Lilongwe, Malawi), Mauro Schechter (Rio de Janeiro, Brazil), John Sidle (Eldoret, Kenya), Eduardo Sprinz (Porto Alegre, Brazil), Besigin Tonwe-Gold (Abidjan, Côte d'Ivoire), Siaka Toure (Abidjan, Côte d'Ivoire), Stefaan Van der Borght (Amsterdam, The Netherlands), Ralf Weigel (Lilongwe, Malawi), and Robin Wood (Cape Town, South Africa)
- Advisory Committee: Zackie Achmat, Chris Bailey, Kevin de Cock, Wafaa El-Sadr, Ken Freedberg, Helene Gayle, Charlie Gilks, Catherine Hankins, Tony Harries, Elly Katabira, Jonathan Sterne, and Mark Wainberg
- Funding: National Institutes of Health Office of AIDS Research (Paolo Miotti and Jack Whitescarver), Agence Nationale de Recherche sur le Sida (ANRS) (Brigitte Bazin), and Canadian Institutes of Health Research (CIHR)
- Collaborating Centers: CEPREF/ANRS COTRAME (Abidjan, Côte d'Ivoire), Centre Hospitalier Universitaire (Casablanca, Morocco), CESAC (Bamako, Mali), CIRBA (Abidjan, Côte d'Ivoire), CORPMED (Lusaka, Zambia), DARVIR (Douala, Cameroon), Heineken International (Amsterdam, The Netherlands), HIVNAT (Bangkok, Thailand), Hospital de Clinicas/SOBRHIV (Porto Alegre, Brazil), Hospital Universitario Clementino Fraga Filho (Rio de Janeiro, Brazil), Independence Surgery Clinic (Gaborone, Botswana), Innovir Institute (Johannesburg, South Africa), ISAARV/ANRS (Dakar, Senegal), Kamuzu Central Hospital/Lighthouse Trust (Lilongwe, Malawi), Makerere-University of California, San Francisco/Generic Antiretroviral Therapy Project (Kampala, Uganda), Military Reference Hospital (Lagos, Nigeria), Moi University College of Health Sciences/University of Indiana (Eldoret, Kenya), Nsambya Hospital (Kampala, Uganda), PARVY/Military Hospital, Médecins Sans Frontières and Institut de Recherche pour le Développement (Yaoundé, Cameroon), PHRU/Opera (Soweto, South Africa), University of Cape Town/CTAC (Cape Town, South Africa), University of Cape Town/Khayelitsha (Cape Town, South Africa), and YRG Care (Chennai, India)