The results of a genotypic resistance test performed before HAART initiation were available for 48 (60%) of those who experienced virological failure. Only one drug resistance mutation was detected (resistance to lamivudine). Conclusive genotypic resistance tests were available for 53 (67%) patients (31 patients receiving a PI-based regimen and 22 an NNRTI). Among these 53 individuals, 32 (60%) were at least resistant to one drug (77% and 48% of those receiving an NNRTI and a PI-based regimen, respectively). Seventeen (77%) NNRTI mutations and 7 (23%) PI mutations were found in patients receiving these drugs. Twenty-one patients (40%) had dual-class resistances. The most common resistance to NRTIs was the mutation M184V to lamivudine (n = 24, 45%). A summary of the different resistances detected is given in Figure 3 and Figure S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A365). It should be noted that no resistance mutation was found in patients with a single VL ≥1000 copies/mL.
At the population level, the estimated cumulative risk of resistance to any drug was 3% (95% CI: 1 to 5) at 12 months, 11% (95% CI: 8 to 15) at 24 months, 16% (95% CI: 13 to 21) at 48 months, and 18% (95% CI: 13 to 21) at 60 months (Fig. 1C). The risk of resistance to any drug was positively associated with AIDS history at baseline and negatively associated with age, baseline CD4-cell count, and adherence (Table 2). As displayed in Figure 2, the relationship between the risk of resistance and adherence level was nonlinear (P = 0.05).
Forty-eight (60%) patients with virological failure and 17 (40%) with no virological suppression were switched to second-line HAART. In the former, the median time between the first VL ≥1000 copies/mL and the treatment switch was 36 months (IQR = 18–54). This delay was larger for the first patients enrolled in the cohort (median delay was 33 months for those enrolled before 2001 versus 18 months for those enrolled after 2001, P < 0.01).
After excluding 7 patients who had been followed up for <6 months and/or had no VL measurement after switching to a second-line regimen and 5 others who achieved an undetectable VL before switching, 53 patients were eventually included in the subanalysis of virological response to second-line HAART. Their regimens included an NNRTI in 30 (57%) patients or a PI otherwise. Among the latter, lopinavir boosted with ritonavir, indinavir, and nelfinavir were used by 39%, 48%, and 13%, respectively. The median follow-up duration for these 53 patients was 45 months, and the median time on first-line HAART was 56 months (IQR = 44–70). Their median CD4-cell count and log10 VL just before or at treatment switch were 239 cells/mm3 (IQR = 103–332) and 4.47 log10 copies/mL (IQR = 4.04–5.00), respectively. Of these 53 patients, 43 (81%) achieved viral suppression <500 copies/mL within a median time of 6 months. All those who did not achieve virological suppression were receiving an NNRTI-based second-line regimen and 9 (90%) were documented as being resistant to at least one drug in their regimen before switching. After achieving virological suppression, 12 patients experienced a second episode of virological failure, which resulted in a cumulative risk of virological failure of 18% (95% CI: 8 to 28) at 6 months, 20% (95%CI: 10 to 30) at 12 months, and 27% (95% CI: 15 to 41) at 24 months (Fig. 1D). All of these patients (except one with no resistance data available) had dual-class resistances before or at the time of virological failure, and 8 (67%) of them were resistant to at least one of their second-line regimen drugs at virological failure. By contrast, their average adherence level was similar to that of patients who did not experience a second episode of virological failure (95% vs. 94.5%, P = 0.6).
In this study, using data from one of the first African cohorts of HIV-1–infected adults started on HAART, we were able to analyze together the virological outcomes for patients who were on first-line HAART for over >5 years and the virological response to second-line HAART. As the rollout of HAART in resource-limited countries continues, such results are important to inform calculations on the expected rate of virological failure and the effectiveness of second-line regimens.
We found that the overall virological response for patients on first-line HAART was good, with >80% of patients achieving virological success. This result is similar to those observed in other African and non-African settings.24–30 The risk of virological failure rose sharply during the first 24 months of HAART then leveled off. This result confirms the importance of monitoring the initial response to treatment more closely. Although the proportion of patients with virological failure estimated was dependent of the definition adopted, drug resistances were observed only when a VL ≥1000 copies/mL was found in 2 consecutives tests, which suggests that this definition might have more clinical significance. Restricted to the first 2 years of follow-up, the estimated proportion of people with resistance to at least one drug in this cohort was similar to those from studies with intensive monitoring (more frequently than every 2 weeks) reported by Gupta et al.31 Over a longer follow-up time (up to 5 years), we found that the cumulative risk of virological failure and resistance was lower than or similar to those reported in high-resource countries.14,29,32–35 However, because of the delay between virological failure and treatment switching, it is likely that resistances' mutations were actually more frequent when the patients were started on second-line HAART. This delay may be attributable to several factors. First of all, the patients included in this cohort were among the first patients started on HAART in Senegal, and the number of drugs available at the beginning of cohort was very limited. Second, although VL and CD4-cell count were used for the monitoring, they were measured only twice a year. This resulted in a delay before a confirmatory VL was obtained, and a decision of switch to a second-line regimen made.
In 1998, indinavir was the only PI-based regimen available. Because it was poorly tolerated and several pills had to be taken daily, impaired adherence and consequently, early virological failure or switches were commonly observed in patients receiving this regimen. Moreover, stavudine that was used in most regimen of this cohort resulted also in frequent adverse events.36 Although our results should be cautiously interpreted, as patients who receive were more likely to be sicker compared with those who receive an NNRTI, they are in line with the results from the PEARLS (ACTG A5175) trial.37 However, it should be noted that despite the higher rate of virological failures, proportionally less resistance mutations were detected in patients receiving a PI-based regimen. The nonlinear relationship between adherence to PI-based regimens and the risk of virological failure or drug resistance found in this study—which is similar to results from other studies34,38—suggests a greater robustness of PI-based regimens to drug resistance at low to moderate levels of adherence, although it is important to note that pills count is a very imperfect proxy for adherence.39 Therefore, antiretroviral regimens based on boosted PI regimens which are more efficient and better tolerated compared with their nonboosted PI counterparts, might be a better alternative to NNRTI-based regimens when adherence is imperfect and when VL monitoring is infrequent, as is the case in many HIV programs in resource-limited settings.40
Outcomes for second-line HAART were not as good as those observed for first-line HAART. Although the proportion of virological success in the former was only slightly lower than that in the latter, the probability of failure while receiving the former was more than twice as high. These results from a cohort of patients from West Africa fall within the range of those reported in a recent meta-analysis by Ajose et al.41 Likewise, we found that virological failure while receiving second-line regimens occurred early on after switching. An important concern is that virological failure occurred in a context of multiple resistances, which underscores the necessity of improving access to third-line regimens in resource-limited settings.
To our knowledge, this is the first study in a resource-limited setting to provide estimates of the risk of virological failure and drug resistance over such a long period. Moreover, because the data were prospectively collected, our estimates are less prone to bias compared with those from cross-sectional studies.33,42 However, several study limitations should be noted when interpreting our results. First, this study had a small population size limiting the precision of our estimates especially over the long term. A relatively large amount of data was missing, including genotypic tests for one-third of those who experienced virological failure. Such a situation is not uncommon,14,17,33 and we used a multiple-imputation approach to account for the missing data.17 Nevertheless, it is important to keep in mind the assumptions made with such a statistical approach: first, it was assumed that all patients with VL <1000 copies/mL had no resistance mutation. Second, multiple imputation only works under the assumption that data were missing at random, conditionally on the observed variables.16 Although it cannot actually be checked, this assumption seems reasonable as most of the tests were missing because of logistic problems.
In conclusion, this study shows good virological outcomes for patients on first-line HAART for over >5 years. However, outcomes for second-line HAART were not as good and most of the virological failure observed with second-line regimens occurred in the context of multiple resistances, emphasizing the importance of intensive monitoring and early adherence support, and the need to improve access to and availability of third-line regimens.
The authors are grateful to Jude Sweeney for his assistance in editing this manuscript.
The ANRS 1215 study group: I. Ndoye (Multisectorial AIDS Program, Dakar, Senegal), Alice Desclaux, E. Delaporte, J. F. Etard, C. Laurent, B. Taverne, M. Peteers, P. De Beaudrap (UMI 233, Research Institute for Development (IRD)/University of Montpellier, Dakar, Senegal and Montpellier, France), M. Basty Fall, A. B. Dieng, A. Diouf, C. Massidi, A. Sarr, L. Zié (Regional Research and Training Center for HIV/AIDS, Fann University Teaching Hospital, Dakar, Senegal), I. Lanièce, M. Meynard (French Ministry of Foreign Affairs, Dakar, Senegal), I. Ndiaye, A. Ndir, C. T. Ndour, C. S. Senghor, P. S. Sow, (Department of Infectious Diseases, Fann University Teaching Hospital, Dakar, Senegal), N. F. Ngom Guèye, (Ambulatory Care Unit-Red-Cross, Fann University Teaching Hospital, Dakar, Senegal), K. Ba Fall, P. M. Guèye, (Military Hospital of Dakar, Senegal), S. Mboup, N. C. Touré Kane (Le Dantec University Teaching Hospital, Virology and Bacteriology Laboratory, Dakar, Senegal), K. Diop, B. Ndiaye (Central Pharmacy, Fann University Teaching Hospital, Dakar, Senegal).
1. Desclaux A, Lanièce I, Ndoye I, et al., eds. The Senegalese Antiretroviral Drug Access Initiative. An Economic, Social, Behavioural and Biomedical Analysis. Paris: France: ANRS, UNAIDS, WHO; 2002.
2. Laurent C, Diakhate N, Gueye NF, et al.. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS. 2002;16:1363–1370.
3. Weidle PJ, Malamba S, Mwebaze R, et al.. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet. 2002;360:34–40.
4. Seyler C, Anglaret X, Dakoury-Dogbo N, et al.. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'Ivoire. Antivir Ther. 2003;8:385–393.
6. Etard JF, Ndiaye I, Thierry-Mieg M, 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.
7. 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. 2006;367:817–824.
8. Keiser O, Chi BH, Gsponer T, et al.. Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in Southern Africa. AIDS. 2011;25:1761–1769.
9. Keiser O, Tweya H, Boulle A, et al.. Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring. AIDS. 2009;23:1867–1874.
10. Hosseinipour MC, van Oosterhout JJ, Weigel R, et al.. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS. 2009;23:1127–1134.
11. Landman R, Canestri A, Thiam S. First evaluation of d4T, ddI and EFZ in antiretroviral naive patients in Senegal: ANRS 1206/IMEA 012 study. Paper presented at: XIIth International Conference on AIDS and STDs in Africa; December 9-13, 2001; Ouagadougou, Africa.
12. 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. 2003;17:1017–1022.
13. Landman R, Poupard M, Diallo M, et al.. Tenofovir-emtricitabine-efavirenz in HIV-I-infected adults in Senegal: a 96-week pilot trial in treatment-naive patients. J Int Assoc Physicians AIDS Care (Chic). 2009;8:379–384.
14. Phillips AN, Dunn D, Sabin C, et al.. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS. 2005;19:487–494.
15. Djoko CF, Rimoin AW, Vidal N, et al.. High HIV type 1 group M pol diversity and low rate of antiretroviral resistance mutations among the uniformed services in Kinshasa, Democratic Republic of the Congo. AIDS Res Hum Retroviruses. 2011;27:323–329.
16. Little RJA, Rubin DB. Statistical Analysis With Missing Data. Hoboken, NJ: Wiley; 2002.
17. Abraham AG, Lau B, Deeks S, et al.. Missing data on the estimation of the prevalence of accumulated human immunodeficiency virus drug resistance in patients treated with antiretroviral drugs in North America. Am J Epidemiol. 2011;174:727–735.
18. Klein J, Moeschberger M. Survival Analysis. Techniques for Censored and Truncated Data. 2nd ed. New York, NY: Springer; 2003.
19. Turnbull B. The empirical distribution function with arbitrarily grouped, censored and truncated data. J R Stat Soc. 1976;38:290–295.
20. Efron B, Tibshirani R. An Introduction to the Bootstrap. New York, NY: Chapman & Hall; 1993.
21. Carstensen B. Regression models for interval censored survival data: application to HIV infection in Danish homosexual men. Stat Med. 1996;15:2177–2189.
22. Wood SN. Generalized Additive Models: An Introduction With R. New York, NY: Chapman & Hall/CRC; 2006.
23. R Development Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2009.
24. Ferradini L, Jeannin A, Pinoges L, et al.. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet. 2006;367:1335–1342.
25. Laurent C, Kouanfack C, Koulla-Shiro S, et al.. Long-term safety, effectiveness and quality of a generic fixed-dose combination of nevirapine, stavudine and lamivudine. AIDS. 2007;21:768–771.
26. Laurent C, Kouanfack C, Laborde-Balen G, et al.. Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised non-inferiority trial. Lancet Infect Dis. 2011;11825–833.
27. 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. 2006;367:817–824.
28. Barth RE, van der Loeff MF, Schuurman R, et al.. Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review. Lancet Infect Dis. 2010;10:155–166.
29. 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. 1999;353:863–868.
30. Paredes R, Mocroft A, Kirk O, et al.. Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study. Arch Intern Med. 2000;160:1123–1132.
31. Gupta RK, Hill A, Sawyer AW, et al.. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:409–417.
32. Mocroft A, Ruiz L, Reiss P, et al.. Virological rebound after suppression on highly active antiretroviral therapy. AIDS. 2003;17:1741–1751.
33. Pillay D, Green H, Matthias R, et al.. Estimating HIV-1 drug resistance in antiretroviral-treated individuals in the United Kingdom. J Infect Dis. 2005;192:967–973.
34. Harrigan PR, Hogg RS, Dong WW, et al.. Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. J Infect Dis. 2005;191:339–347.
35. Richman DD, Morton SC, Wrin T, et al.. The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004;18:1393–1401.
36. Mercier S, Gueye NF, Cournil A, et al.. Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case-control study. J Acquir Immune Defic Syndr. 2009;51:224–230.
37. Campbell T, Smeaton L, De Grutolla V. PEARLS (ACTG A5175): a multinational study of didanosine-EC, emtricitabine and atazanavir vs. co-formulated zidovudine/lamivudine and efavirenz for initial treatment of HIV-1 infection. Paper presented at: XVII International AIDS Conference 2008; August 3-8, 2008; Mexico City, Mexico.
38. King MS, Brun SC, Kempf DJ. Relationship between adherence and the development of resistance in antiretroviral-naive, HIV-1-infected patients receiving lopinavir/ritonavir or nelfinavir. J Infect Dis. 2005;191:2046–2052.
39. Gardner EM, Burman WJ, Steiner JF, et al.. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23:1035–1046.
40. Adlington R, Richens J, Shahmanesh M. First-line antiretroviral therapy in resource-limited settings: time to reconsider? J Infect Dis. 2009;199:1407; Author reply–8.
41. Ajose O, Mookerjee S, Mills EJ, et al.. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. AIDS. 2012;26:929–938.
42. Harrigan PR, Wynhoven B, Brumme ZL, et al.. HIV-1 drug resistance: degree of underestimation by a cross-sectional versus a longitudinal testing approach. J Infect Dis. 2005;191:1325–1330.