Data on the clinical consequences for patients of harbouring resistant virus while being on HAART have never been reported in Africa.
Among our patients on HAART for a median of 3 years in Abidjan, Côte d’Ivoire, 58% had undetectable viral loads, 20% had detectable viral loads with no major resistance mutations and 22% had major drug resistance mutations. In the following 20 months, patients with major mutations had higher rates of immunological failure and tended to have higher rates of serious morbidity, but their CD4 cell counts remained stable and only one of them died.
These findings deserve the following comments.
In our population, one out of five patients harboured major resistance mutations after a median time on HAART of 3 years. This rate is in the lower bracket of those previously reported from other sub-Saharan African settings, in patients with similar or shorter times on HAART [4,6–8,16–18]. Differences between African settings in terms of the rate of patients with resistance mutations may depend on various determinants. Our study did not aim at identifying these determinants, which still remain to be carefully studied.
The main objective of our study was to analyse the association between the presence of resistance mutations and treatment outcomes. To our knowledge, this has never been done in sub-Saharan Africa so far. Studies of outcomes in patients with resistance mutations are likely to reach different conclusions depending on the type and number of drugs affected and on the range of drugs available in a given setting. In industrialized countries, some studies found an association between drug resistance mutations and an increased risk of death or new AIDS-defining event/death [19,20], whereas others did not find any association between drug resistance mutations and clinical outcomes [21,22]. In Abidjan, Côte d’Ivoire, during the study period, the number of available antiretroviral drugs was limited. Several large programmes of access to HAART were being launched, but the country was experiencing a severe political crisis. In this context, only 43% of patients with major resistance mutations at baseline experienced a change in their HAART regimen, and had a chance that a consecutive reduction in viral load could lead to better immunological and clinical outcomes. The remaining 57% of patients with major resistance could not have their drug regimen appropriately adapted to the genotypic tests results during the study period. The consequences were as follows. On one hand, the 20-month clinical and immunological outcomes of patients with resistance at baseline were clearly compromised compared with patients with no resistance. On the other hand, these patients with resistance mutations had reasonable viral load values at baseline (median 3.7 log10 copies/ml). During the 20-month follow-up, their CD4 cell counts remained stable and close to 200 cells/μl. Although they tended to have higher morbidity rates, most were curable diseases, and only one patient died. In other words, their medium-term outcomes were impaired compared with patients without resistance mutations, but their antiretroviral treatment still protected them from immunological breakdown. The main reason for this is probably that they continued to receive at least one or two antiretroviral drugs against which their viruses had no resistance. Other reasons could be the poorer capacity of the replication of resistant virus compared with wild-type viruses [23,24], and the preservation of some in-vivo effects of some drugs on viruses showing in-vitro resistance [25,26]. In patients with virological failure, even a limited reduction in viral load has been shown to be of importance .
Our study has the following limitations. First, patients who participated in the study were part of a group of patients who started HAART while they were followed in a cohort study between 1998 and 2003. Patients from this cohort who died or who were lost to follow-up before July 2004 could not be included in the present study. Among these patients, the rate of resistance mutations was unknown. Therefore, our conclusion that there is immunological stability among the patients with resistance mutations cannot apply to all patients who started HAART, but only to patients who survived and remained in care during a median of 37 months after HAART initiation. Second, our study included patients receiving different regimens of HAART and with different histories of regimen modification since HAART initiation. Our sample size was too limited to adjust the analysis of the association between resistance and outcomes on these variables. Further studies comparing outcomes in patients with and without resistance mutations should include a sufficient number of patients to allow adjustment on antiretroviral drugs received by the patients. Third, in our study, viral load was only measured at baseline, and adherence to HAART was not measured. In further studies, viral load and adherence evolution should be carefully recorded. In patients with detectable viral loads but no major resistance mutation and in those with major resistance who experience a change in their HAART regimen, the rate of virological success would be likely to be associated with improved adherence.
Our findings have the following consequences on ‘when to change a failing regimen’ in sub-Saharan Africa.
In settings in which resistance tests are routinely available, drugs can be spared by an early selective substitution of the drugs against which the virus strains have been shown to be resistant through genotypic tests. In sub-Saharan Africa, although CD4 cell measurement is becoming increasingly available, viral load measurement is still rarely available, and genotypic resistance tests are almost never available. Within the following years, millions of sub-Saharan African adults will receive HAART. In these patients, changing regimens for treatment failure will have to be based on clinical outcomes, with the help of CD4 cell counts in most settings and of viral load measurements in some settings. In these patients, the timing of the acquisition of resistance mutations and the number of mutations will be impossible to determine. Failing therapeutic regimens will be maintained during incompressible periods of time, thus increasing drug resistances [28,29]. In this context, the decision of when to change a failing regimen should not be based on the possibility of sparing some drugs of the failing regimen, but should only focus on the risk for a patient to continue a given failing regimen until an entirely new regimen can be proposed to him or her. Our data suggest that most patients with major drug resistance mutations might maintain stable CD4 cell counts and stay alive for more than one year. In low resource settings with restricted access to second-line antiretrorival regimens, the decision to change a failing regimen could be taken within months. This should be taken into account in further cost-effectiveness analyses of HAART in sub-Saharan Africa .
2. Nkengasong JN, Adje-Toure C, Weidle PJ. HIV antiretroviral drug resistance in Africa. AIDS Rev 2004; 6:4–12.
3. Toni T, Masquelier B, Bonard D, Faure M, Huet C, Caumont A, et al
. Primary HIV-1 drug resistance in Abidjan (Cote d’Ivoire): a genotypic and phenotypic study. AIDS 2002; 16:488–491.
4. Vergne L, Kane CT, Laurent C, Diakhate N, Gueye NF, Gueye PM, et al
. Low rate of genotypic HIV-1 drug-resistant strains in the Senegalese government initiative of access to antiretroviral therapy. AIDS 2003; 17(Suppl 3):S31–S38.
5. Bellocchi MC, Forbici F, Palombi L, Gori C, Coelho E, Svicher V, et al
. Subtype analysis and mutations to antiviral drugs in HIV-1-infected patients from Mozambique before initiation of antiretroviral therapy: results from the DREAM programme. J Med Virol 2005; 76:452–458.
6. Adje C, Cheingsong R, Roels TH, Maurice C, Djomand G, Verbeist W, et al
. High prevalence of genotypic and phenotypic HIV-1 drug-resistant strains among patients receiving antiretroviral therapy in Abidjan, Cote d’Ivoire. J Acquir Immune Defic Syndr 2001; 26:501–506.
7. Vergne L, Malonga-Mouellet G, Mistoul I, Maroungou R, Mansaray H, Peeters M, et al
. Resistance to antiretroviral treatment in Gabon: need for implementation of guidelines on antiretroviral therapy use and HIV-1 drug resistance monitoring in developing countries. J Acquir Immune Defic Syndr 2002; 29:165–168.
8. Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Douning R, et al
. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients’ response, survival, and drug resistance. Lancet 2002; 360:34–40.
9. Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, 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.
10. Anglaret X, Messou E, Ouassa T, Toure S, Dakoury-Dogbo N, Combe P, et al
. Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving cotrimoxazole prophylaxis in Abidjan, Cote d’Ivoire. AIDS 2003; 17:575–584.
11. Anglaret X, Dakoury-Dogbo N, Bonard D, Toure S, Combe P, Ouassa T, et al
. Causes and empirical treatment of fever in HIV-infected adult outpatients, Abidjan, Cote d’Ivoire. AIDS 2002; 16:909–918.
12. Anglaret X, Toure S, Gourvellec G, Tchehy A, Zio L, Zaho M, et al
. Impact of vital status investigation procedures on estimates of survival in cohorts of HIV-infected patients from Sub-Saharan Africa. J Acquir Immune Defic Syndr 2004; 35:320–323.
13. Rouet F, Ekouevi DK, Chaix ML, Burgard M, Inwoley A, Tony TD, et al
. Transfer and evaluation of an automated, low-cost real-time reverse transcription–PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting. J Clin Microbiol 2005; 43:2709–2717.
14. Bile EC, Adje-Toure C, Borget MY, Kalou M, Diomande F, Chorba T, Nkengasong HN. Performance of drug-resistance genotypic assays among HIV-1 infected patients with predominantly CRF02_AG strains of HIV-1 in Abidjan, Cote d’Ivoire. J Clin Virol 2005; 32:60–66.
15. Johnson VA, Brun-Vezinet F, Clotet B, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14:125–130.
16. Richard N, Juntilla M, Abraha A, Demers K, Paxinos E, Gadovitch J, et al
. High prevalence of antiretroviral resistance in treated Ugandans infected with nonsubtype B human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 2004; 20:355–364.
17. Laurent C, Kouanfack C, Vergne L, Tardy M, Zekeng L, Noumsi N, et al
. Antiretroviral drug resistance and routine therapy, Cameroon. Emerg Infect Dis 2006; 12:1001–1004.
18. Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, et al
. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet 2006; 367:1335–1342.
19. Zaccarelli M, Tozzi V, Lorenzini P, Trotta MP, Forbici F, Visco-Comandini U, et al
. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 2005; 19:1081–1089.
20. Hogg RS, Bangsberg DR, Lima VD, Alexander C, Bonner S, Yip B, et al
. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med 2006; 3:e356.
21. Lucas GM, Gallant JE, Moore RD. Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing. AIDS 2004; 18:1539–1548.
22. Machouf N, Thomas R, Nguyen VK, Trottier B, Boulassel MR, Wainberg MA, Routy JP. Effects of drug resistance on viral load in patients failing antiretroviral therapy. J Med Virol 2006; 78:608–613.
23. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000; 181:946–953.
24. Cozzi-Lepri A, Phillips AN, Miller V, Katlama C, Ledergerber B, Vella S, et al
. Changes in viral load in people with virological failure who remain on the same HAART regimen. Antivir Ther 2003; 8:127–136.
25. Martinez-Picado J, Savara AV, Sutton L, D’Aquila RT. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 1999; 73:3744–3752.
26. Deeks SG, Wrin T, Liegler T, Hoh R, Hayden M, Barbour JD, et al
. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344:472–480.
27. Ledergerber B, Lundgren JD, Walker AS, Sabin C, Justice A, Reiss P, et al
. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004; 364:51–62.
28. Kantor R, Shafer RW, Follansbee S, Taylor J, Shilane D, Hurley L, et al
. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS 2004; 18:1503–1511.
29. Goetz MB, Ferguson MR, Han X, McMillan G, St Clair M, Pappa KA, et al
. Evolution of HIV resistance mutations in patients maintained on a stable treatment regimen after virologic failure. J Acquir Immune Defic Syndr 2006; 15:541–549.
30. Goldie SJ, Yazdanpanah Y, Losina E, Weinstein MC, Anglaret X, Walensky RP, et al
. Cost-effectiveness of HIV treatment in resource-poor settings-the case of Cote d’Ivoire. N Engl J Med 2006; 355:1141–1153.