To the Editor:
Thymidine nucleoside analogues have been the backbone of most highly active antiretroviral therapy (HAART) regimens for several years. Reported associations of stavudine and, to a lesser degree, zidovudine with mitochondrial toxicity, lipoatrophy, and certain metabolic changes have favored the use of nonthymidine nucleoside analogues as first-line compounds, however.1,2 Tenofovir (TDF)- and abacavir (ABC)-containing regimens combined with emtricitabine (FTC) or lamivudine (3TC) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) have shown good efficacy and tolerability in several clinical trials and are now extensively used in nucleoside fixed-dose combinations as part of first-line regimens.2-5
The physician's choice of the first nucleoside reverse transcriptase inhibitor (NRTI) option may be influenced by the intrinsic toxicity of these agents: hypersensitivity reactions with ABC and renal toxicity with TDF. Another factor that may have an impact on the choice of a first regimen is the resistance profile, which can condition future sequencing options. In patients with virologic failure, the key mutations selected are K65R in those receiving TDF (although it is rare in 2-class regimens) and L74V, Y115F, and K65R in those receiving ABC. Emergence of these mutations raises concern as to the efficacy of the next options used. K65R selection occurs less commonly with administration of ABC/3TC than with TDF, but the association of L74V and M184V typically compromises ABC and didanosine (ddI) activity. Although ABC/3TC/EFV has been evaluated in clinical trials, extensive data regarding its resistance profile are not available.4,5
Primary resistance to antiretrovirals may contribute to virologic failure. Several studies have recently shown an increase in primary resistance rates in various geographic areas,6,7 and a genotypic resistance test is now recommended before initiation of HAART in patients with chronic HIV infection.8
The ABCDE study was a 96-week, randomized, multicenter trial performed in a cohort of antiretroviral-naive patients, where ABC was compared with stavudine, both associated with 3TC/efavirenz (EFV).9 The patients receiving ABC presented with a notably lower incidence of lipoatrophy and a better lipid profile. In addition, a trend favoring ABC was observed in the intent-to-treat analysis when comparing the proportion of patients with a viral load <50 copies/mL.9 The incidence and patterns of resistance mutations at baseline and at virologic failure were also assessed in this study and are presented herein.
Among the 237 patients enrolled in the trial up to June 2002, genotype resistance testing (ViroSeq HIV-1 genotyping system; Abbott Diagnostics, Abbott Park, IL) was performed in 227 (96%) patients at baseline and in those with virologic failure and a confirmed HIV-1 RNA load >500 copies/mL. The International AIDS Society (IAS) algorithm (August 2006)10 was used to evaluate the presence of mutations associated with resistance.
Among the 227 patients with genotype testing at baseline, several resistance mutations were detected alone or in combination in 12 (5.3%) patients. Mutations associated with nucleoside analogue resistance were observed in 9 (4%) patients, and mutations associated with NNRTI resistance were observed in 3 (1.3%). No major PI-associated resistance mutations were detected (Table 1).
Twenty-seven (12%) patients presented with virologic failure during follow-up. In 7 patients, the HIV-1 RNA level was 50 to 500 copies/mL, and in 1 case, the HIV-1 RNA level could not be amplified. Thus, genotype resistance results were available in 19 patients. In 12 patients (63%), no resistance mutations were detected, and in all cases, there had been poor adherence and/or discontinuation of therapy. Five of the 12 patients reinitiated the same regimen, reaching an HIV-1 RNA level <50 copies/mL after a median period of 3 months.3-6 Resistance mutations were detected in 7 of the 19 patients with virologic failure and resistance testing (37%); 5 were new (not detected at baseline) resistance mutations, as detailed in Table 1.
Overall, virologic failure occurred in 4 (33.3%) of 12 patients with resistance mutations at baseline; these included 2 of 9 patients with baseline mutations associated with nucleoside analogue resistance and 2 of 3 patients with baseline mutations associated with NNRTI resistance. The fact of not presenting with primary resistance was associated with a significantly lower risk of virologic failure (odds ratio [OR] = 0.028, 95% confidence interval [CI]: 0.005 to 0.148). The mutation pattern seen at failure in patients with or without baseline resistance mutations is shown in Table 1.
With regard to NNRTIs, both patients with the K103N mutation at baseline failed at 6 and 12 months (in the first case, the M184V mutation was also selected at failure). Nevertheless, it is interesting that the patient with the Y181C mutation, which confers high-level resistance to delavirdine and nevirapine, but only low-level resistance to EFV, had a durable virologic response up to the end of the study period.
Summarizing the results, in this 96-week trial, only 3% (7 of 227) of patients had virologic failure associated with the presence of resistance mutations. Most patients with virologic failure and a viral load >500 copies/mL were poorly adherent; hence, the drug pressure on HIV, if any, did not suffice to develop resistance. Of note, K65R and L74V were not selected during the study period. Stavudine did not show an advantage in terms of resistance as compared with ABC. Although the prevalence of resistance mutations at baseline was relatively low (mainly regarding NNRTI-associated resistance), their presence had a clinical impact, with one third of the patients presenting with virologic failure.
Our results agree with previous studies showing that ABC/3TC/EFV is associated with a low incidence of virologic failure related to the development of resistance mutations, with M184V- and EFV-associated mutations being the most prevalent. The absence of K65R and L74V also fits in with results from other clinical trials, which have reported a low prevalence of these mutations.4,11
Recent reports from the United States and Europe have indicated that the prevalence of HIV-1 primary resistance to antiretroviral drugs is growing, at least in some geographic areas.6,7 We did not detect this trend, particularly with respect to NNRTI resistance. It should be noted that our patients were enrolled up to mid-2002 and that some changes in the prevalence of primary resistance may have occurred over the past years. Our data agree with recent Spanish reports, however, in which a reduction or at least a stabilization of primary resistance rates has been observed in recent HIV-1 seroconverters, ranging from 33% in 1997 to 7.7% in 2004.12,13 In another multicenter study with newly diagnosed HIV-infected patients from January 2004 onward, the prevalence of primary resistance was only 4%.14 These data may vary in the future; thus, surveillance studies should be conducted to identify modifications in the prevalence of primary mutations associated with resistance.
It has been suggested that standard methods may not detect the presence of minor baseline populations of reverse transcriptase- or PI-resistant strains, which may be associated with subsequent virologic failure.15,16 If this was the case in this trial, few patients seem to have been affected, because only 4 (1.8%) of 224 developed NNRTI-associated mutations at virologic failure in the absence of resistance mutations at baseline.
Finally, although the proportion of patients with baseline resistance was low, the rate of virologic failure in these patients, mainly when NNRTI mutations were present, highlights the benefits of performing genotype resistance testing in naive patients, particularly if an NNRTI-containing regimen is given.
In conclusion, a small incidence of resistant mutations at failure and a resistance pattern preserving most therapeutic options, together with its known efficacy and tolerability, are the advantages of ABC/3TC/EFV as a first-line regimen. At present, at least in our area, the resistance profile seems to have a lower impact than other factors on clinical decisions regarding the best HAART options to give to naive patients.
Elena Ferrer, MD*
Jordi Niubo, PharmD*
Manuel Crespo, MD†
Josep Maria Gatell, MD‡
Jose Sanz, MD§
Sergio Veloso, MD∥
Josep Maria Llibre, MD¶
Pilar Barrufet, MD#
Pochita Sanchez, RN*
Daniel Podzamczer, MD*
for the ABCDE Study Team
*Hospital Universitari de Bellvitge Barcelona, Spain
†Hospital Vall d'Hebron Barcelona, Spain
‡Hospital Clinic Barcelona, Spain
§Hospital Principe de Asturias Alcalá de Henares, Spain
∥Hospital Joan XXIII Tarragona, Spain
¶Hospital Calella Barcelona, Spain
#Hospital Mataro Barcelona, Spain
1. Mallal SA, John M, Moore CB, et al. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS
2. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med
3. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs. stavudine in combination therapy in antiretroviral-naive patients. A 3-year randomized trial. JAMA
4. DeJesus E, Herrera G, Teofilo E, et al, for the CNA30024 Study Team. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis
5. Moyle G, DeJesus E, Cahn P, et al, for the Ziagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study Team. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once-Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr
6. Novak RM, Chen L, McArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronic HIV-infected, treatment naive patients, implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis
7. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis
8. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection. 2006 recommendations of the International AIDS Society-USA Panel. JAMA
9. Podzamczer D, Ferrer E, Sanchez P, et al. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. J Acquir Immune Defic Syndr
10. Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: fall 2006. Top HIV Med
11. Irlbeck D, Rouse E, Castillo S, et al. Treatment emergent mutations for previously naive HIV-infected adults failing ZDV+3TC+EFV and ABC+3TC+EFV [CNA30024]. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; 2004; San Francisco.
12. de Mendoza C, Rodriguez C, Eiros JM, et al. Antiretroviral recommendations may influence the rate of transmission of drug-resistant HIV type 1. Clin Infect Dis
13. De Mendoza C, Rodríguez C, Colomina J, et al. Resistance to non-nucleoside reverse transcriptase inhibitors and prevalence of HIV type 1 non-B subtypes are increasing among persons with recent infection in Spain. Clin Infect Dis
14. Martinez-Picado J, Gutierrez C, de Mendoza C, et al. Surveillance of drug resistance and HIV subtypes in newly diagnosed patients in Spain during 2004. Antivir Ther
15. Metzner KG, Rauch P, Walter H, et al. Detection of minor populations of drug-resistant HIV-1 in acute seroconverters. AIDS
16. Johnson J, Li JF, Wei X, et al. Low-frequency mutations substantially increase the prevalence of transmitted drug resistance and greatly strengthen the relationship between resistance mutations and virologic failure. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; 2007; Los Angeles.