Thymidine analogue mutations in antiretroviral-naive HIV-1 patients on triple therapy including either zidovudine or stavudine

Laurence Bocket1,*, Yazdan Yazdanpanah2,3, Faïza Ajana2, Yann Gerard2, Nathalie Viget2, Anne Goffard1, Isabelle Alcaraz2, Pierre Wattré1 and Yves Mouton2

1 Service Universitaire de Virologie, Centre Hospitalier Régional de Lille, Lille; 2 Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Tourcoing; 3 Centre de Recherches Economiques, Sociologiques et de Gestion, Labores, CNRS U362, Lille, France

Received 11 July 2003; returned 22 August 2003; revised 8 September 2003; accepted 3 October 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Aims: The aims of this study were to: (i) determine the incidence of thymidine-associated mutations (TAMs) in an observational clinical cohort of naive HIV-1 patients who stopped first-line therapy including either zidovudine or stavudine; and (ii) assess the immunological and virological responses to subsequent second-line therapy in patients who switched from zidovudine to stavudine or conversely.

Patients and methods: Plasma samples from 165 patients who stopped first-line antiretroviral therapy containing either zidovudine or stavudine were examined for the presence of drug-resistant genotypes. Subsequent second-line immunological and virological follow-up was performed in 136 patients who switched from zidovudine to stavudine and conversely.

Results: Among the 93 patients who stopped first-line therapy including zidovudine and the 72 who stopped first-line therapy including stavudine, genotypic resistance testing was available for 67 (72%) and 54 (75%), respectively. The presence of TAMs was significantly more frequent in the zidovudine than the stavudine group (23.8% versus 5.5; P = 0.006). The short- and long-term immunological and virological responses to second-line therapy were comparable in the zidovudine and stavudine groups, despite different baseline profiles of viral resistance (median increase in CD4 cells/mm3 at 1 year of therapy, 118 versus 119; viral load <400 copies/mL, 47% versus 47%).

Conclusions: These results suggest that TAMs occur in more patients on antiretroviral regimens including zidovudine than on regimens including stavudine. Although the results from observational studies should be interpreted cautiously, these findings may be useful in determining the optimal sequencing of zidovudine and stavudine for the treatment of naive HIV-1-infected patients.

Keywords: HIV-1 drug resistance, antiretroviral therapy, zidovudine, stavudine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Highly active antiretroviral therapy (HAART) in patients with human immunodeficiency virus (HIV) disease is currently based on a combination including two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a third NRTI.1,2 Until recently, the available NRTIs recommended by International AIDS Society—USA Panel Guidelines were zidovudine (AZT) or stavudine (d4T) for inclusion in regimens used as first-line antiretroviral therapy in HIV-1-naive patients.1 However, these NRTIs induce the emergence of viral drug resistance that is caused by mutations, called either thymidine analogue mutations (TAMs) or nucleoside analogue mutations (NAMs) because of these mutations’ involvement in NRTI cross-resistance.3,4 It is not clear whether the incidence of TAM occurrence is associated with the type of NRTI used in the first regimen. The question that therefore arises is whether to begin with zidovudine or stavudine in order to preserve future options for subsequent regimens.5

In this study, we evaluated in HIV-1-infected patients the impact of the NRTI used in first-line triple therapy on TAM occurrence, and also the virological and immunological response to second-line therapy, using a clinical database from the Tourcoing AIDS Reference Center, northern France.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients

All patients referred to the Tourcoing AIDS Reference Center from January 1996 to December 2001 who had HIV-1 infection confirmed by western blot, were >13 years of age, and who had received a first-line antiretroviral therapy including either zidovudine or stavudine, were enrolled in this study. Details of this cohort have been published elsewhere.6 In brief, available data included age, sex, probable transmission route of viral infection, year of diagnosis, date of AIDS-defining events prior to inclusion, CD4 lymphocyte count and HIV viral load at inclusion. Follow-up data were collected at each outpatient visit, hospital admission or at least every 6 months, by trained technicians who abstracted the information onto standardized computer records. These data included the occurrence of AIDS-defining events, adverse drug-related events, CD4 lymphocyte counts, HIV viral load, and the initiation and discontinuation of therapies.

The study was approved by the ethics committee at the Faculty of Medicine, Lille University, Lille, France.

Methods

To evaluate the impact of the NRTI used in the first triple therapy regimen on the incidence on TAM occurrence, HIV RNA was genotyped in those patients who stopped this therapy because of either virological failure or adverse event attributed to antiretroviral drugs. In addition, we assessed the virological and immunological efficacy of the switch from first-line therapy containing zidovudine to second-line therapy containing stavudine, and conversely.

Plasma HIV-1 RNA levels were measured by quantitative RT–PCR, using the HIV Amplicor Monitor kit, version 1.5 (Roche Diagnostics, Meylan, France), with a lower limit of detection of 400 copies/mL in the usual procedure and 50 copies/mL in the ultrasensitive procedure. Results were expressed as number of copies/mL and log10. Virological efficacy was measured upon the variations in the viral load on the basis of either a reduction greater than 0.5 log10 copies/mL (delta viral load >0.5 log10 copies/mL), or a decrease to below the 400 copies/mL threshold. We assessed the short- and long-term efficacy of the second-line regimen using HIV RNA 12 and 52 weeks after the initiation of this regimen. Changes in the CD4 lymphocyte count were determined at the same time points. CD4 lymphocytes were counted by standard flow cytometry.

Genotypic resistance testing was retrospectively performed for all patients who stopped their first-line therapy. For this, we used stored plasma drawn for viral load quantification during the period from 3 months before to the date at which the first-line therapy was resumed. All plasma samples were stored at –80°C. These samples were not available for all patients and testing was not possible for those with <400 copies/mL of HIV RNA. Consequently, we performed a sensitivity analysis in which we considered that TAMs had occurred in all patients for whom plasma samples were missing. HIV-1 genotype results were obtained using the Visible Genetics TRUGENE HIV-1 Genotype Kit and OpenGene DNA Sequencing System. Mutation patterns were interpreted according to the French ANRS AC11 genotype interpretation guidelines.2 We focused on the main resistance-associated mutations, namely the RT and PR genes. For the RT gene, we first studied the following NRTI mutations: (i) TAMs (M41L, D67N, K70R, L210W, T215Y/F and K219Q/E); (ii) M184V (lamivudine resistance); (iii) V75M/S/A/T (stavudine resistance); and (iv) multidrug resistance mutations (Q151M and codon 69 insertion). Next, we focused on the primary NNRTI mutations associated with resistance to nevirapine and/or efavirenz (L100I, K101E, K103N, Y181C/L, Y188C/H/L, G190A/C/E/Q/S/T/V and P225H). For the PR gene, we studied the following primary resistance mutations: D30N, M46I/L, G48V, I50V, V82A/F/S/T, I84V, N88S/D and L90M.

Statistical analysis

Fisher’s exact test was used to compare proportions. Quantitative variables summarized by median values were compared by the Wilcoxon rank sum test. Time to virological failure on the first-line regimen was calculated using the Kaplan–Meier method and estimates from stavudine and zidovudine group were compared by the log rank test. A P value of <0.05 (two-tailed) was considered significant. Statistical analysis was performed with SAS software (SAS Institute, Cary, NC, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics

In all, 405 antiretroviral-naive patients were enrolled in the Tourcoing clinical cohort from January 1996 to December 2001. Of these, 252 (62.2%) began their first-line therapy with a triple drug combination containing zidovudine, and 153 (37.8%) with a triple drug combination containing stavudine. The baseline characteristics of these patients are reported in Table 1. The patients in both groups were similar in terms of age, gender and probable route of infection. However, fewer patients in the zidovudine than in the stavudine group had a history including an AIDS-defining event. In addition, zidovudine group patients had a higher CD4 cell count and a lower viral load. At baseline, stavudine was more frequently combined with a PI than zidovudine (stavudine–PI 85.6% versus zidovudine–PI 62%; P < 0.001).


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Table 1. Baseline characteristics of 405 antiretroviral-naive patients enrolled in the Tourcoing clinical cohort from January 1996 to December 2001 
 
Discontinuation of the first-line regimen

Overall, during the 5 year study period, 165 (40.7%) patients stopped their first-line therapy, 11 (2.7%) died and 40 (9.9%) were lost to follow-up. During this period, the remaining 189 patients continued on the same treatment regimen (123 with zidovudine and 66 with stavudine). Of the 165 who stopped their first-line therapy, 93 were in the zidovudine group (36.9% of those on an zidovudine-containing regimen) and 72 in the stavudine group (47.1% of those on a stavudine-containing regimen) (P = 0.048). However, the time to virological failure was not different between the stavudine and zidovudine groups (6.8% in the stavudine group versus 6.2% in the zidovudine group at 2 years; P = 0.948, log rank test). In the zidovudine group, the median duration of antiretroviral therapy before discontinuation was 44.3 weeks. Of the 93 patients in this group, discontinuation was related to virological failure in 18 (19.4%), adverse events in 43 (46.2%) and patient decision in 32 (34.4%). In the stavudine group, the median duration of antiretroviral therapy before discontinuation was 44.7 weeks. In this group of 72 patients, discontinuation was related to virological failure in six (8.3%), adverse events in 45 (62.5%) and patient decision in 21 (29.2%).

The characteristics of the patients who stopped their first-line regimen are shown in Table 2. At baseline, median CD4 cell counts were higher and median viral load lower in patients on zidovudine than in those on stavudine (CD4: 285 versus 203 cells/mm3, P = 0.023; viral load: 5.1 versus 5.3 log10 copies/mL, P = 0.01). At the time when treatment was discontinued, the viral load was slightly but significantly lower in the stavudine group, whereas there were no differences between the two groups as regards the CD4 cell count.


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Table 2. Characteristics of 165 patients in the Tourcoing clinical cohort who stopped first-line antiretroviral therapy between January 1996 and December 2001, and number of TAMs in these patients
 
Genotypic resistance at first-line therapy discontinuation

Among the 93 patients who stopped first-line therapy including zidovudine and the 72 who stopped first-line therapy including stavudine, genotypic resistance testing was available for 67 (72%) and 54 (75%) patients, respectively. The presence of TAMs was significantly more frequent in the zidovudine than the stavudine group (23.8% versus 5.5%; P = 0.006) (Table 2). This difference remained significant if we considered that all patients for whom genotypic resistance tests were not available (i.e. 26 in the zidovudine group and 18 in the stavudine group) had TAMs (45% versus 29; P = 0.05).

M184V mutations were more frequently observed in the zidovudine (n = 13) than the stavudine group (n = 4), although the difference was not significant (19.4% versus 7.4%). However, lamivudine was more often associated with zidovudine than stavudine. Thus, when we looked at the occurrence of the M184V mutation in the subgroup of patients who received lamivudine, no differences were found between the two groups (29.6% versus 33.3%; P = 1). There were neither V75M/S/A/T mutations in the stavudine group, nor multidrug resistance mutations in the zidovudine or stavudine group.

In the subgroup of patients who received NNRTIs, primary mutation to NNRTIs was more frequent in the zidovudine than the stavudine group [66.7% (10/15) versus 40% (4/10): P = 0.24]. The same trend was observed in patients given PIs, with more frequent PI primary mutations in the zidovudine group, although the difference was not significant [24.5% (13/53) versus 18.1% (8/44); P = 0.47).

Genotypic resistance testing was available for all patients in whom discontinuation was related to virological failure. In the zidovudine group, we identified the presence of TAMs in 12 of the 18 patients in whom discontinuation was related to virological failure (versus four of 49 patients without virological failure and a genotypic resistance test available; 66.7% versus 8.1%). In five of the remaining patients we identified other major primary mutations: M184V (three), K103N (one), and D30N + M184V (one). No resistance mutations were found in one patient. In the stavudine group we identified the presence of TAMs in two of the six patients with virological failure (versus one of 48 patients without virological failure; 33% versus 2%). In the other patients with virological failure we identified two primary PI resistance mutations and one M184V mutation. No resistance mutations were found in one patient. Overall, the presence of three or more TAMs (n = 6) and particular TAMs such as T215Y (n = 8), M41L (n = 4) and L210W (n = 2) were always associated with virological failure, although we should be cautious in the interpretation of these results because of the small sample size of this study.

Virological and immunological efficacy of the second-line regimen

The immunological and virological responses of patients who switched from zidovudine to stavudine or from stavudine to zidovudine are shown in Table 3. The increase in the number of CD4 cells was similar in the two groups during second-line therapy. Although at baseline TAMs were more frequent in patients on a regimen containing stavudine than on one containing zidovudine, in the short and long term, the virological efficacy of the two regimens was comparable. At week 52, the proportion of patients with undetectable viraemia rose from 18% to 47% among patients on stavudine (+29%) and from 28% to 47% among those on zidovudine (+19%). Among patients on second-line therapy containing stavudine for whom genotypic resistance testing was available (n = 55), the increase in the proportion of patients with undetectable viraemia was similar in those with (n = 13) and without (n = 42) TAMs at baseline (+31% versus +33.3%). At week 52 of the subsequent stavudine therapy, of 13 patients on initial zidovudine therapy who developed TAMs, four had undetectable viraemia (31%) and seven had a viral load decrease superior to 0.5 log10 copies/mL (53.8%). This analysis was not conducted in the group on second-line therapy including zidovudine because only two patients had mutated viruses.


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Table 3. Immunological and virological responses to second-line therapy by 136 patients in the Tourcoing clinical cohort, from January 1996 to December 2001
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this observational study of naive HIV-1 patients on antiretroviral therapy, we evaluated first the impact of the NRTI (zidovudine or stavudine) used in first-line triple therapy on the occurrence of TAMs, and secondly the virological and immunological responses to second-line therapy in patients who switched from zidovudine to stavudine and conversely. In the first-line therapy, the incidence of TAM emergence in viral strains was higher in patients on zidovudine than in those on stavudine. In the second-line therapy the short- and long-term immunological and virological efficacy of the treatment were comparable in the zidovudine and stavudine groups despite the higher frequency of viruses containing TAMs in the latter group (i.e. stavudine second line). Moreover, in patients on second-line therapy on stavudine, the presence of TAM viruses did not affect the efficacy of the treatment.

Several other studies have focused on the emergence of resistance to NRTIs in first-line regimens (Table 4).414 Overall, the occurrence of TAMs in these studies ranged from 0 to 80% at 1 year. In general, genotypic resistance was greater in patients on a dual NRTI regimen than in patients on HAART (30–80% versus 0–33%).414 Although we recognize the need for caution when comparing the results of these studies with our results because of differences in methodology, the frequency of TAM occurrence in our population is consistent with the frequencies reported elsewhere for naive HIV-1 patients receiving HAART.


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Table 4. TAM occurrence at treatment discontinuation in naive HIV-1 patients on first-line dual or triple antiretroviral therapy
 
In our study, the incidence of TAM emergence was higher in patients on first-line triple therapy including zidovudine than on therapy including stavudine. In patients receiving HAART, most authors reported genotypic resistance with zidovudine and stavudine backbone regimens (Table 4), in proportions ranging from 0% to 33% and 0% to 17%, respectively. However, comparisons of the resistance occurring in stavudine- and zidovudine-containing regimens based on these results should be avoided, because of the differences between the baseline characteristics of the patients enrolled, the definition of patients tested for resistance and the duration of follow-up. In addition, small numbers of patients were enrolled in these studies so that estimations derived from them are unreliable.

The occurrence of TAMs has been compared in patients on stavudine- and zidovudine-containing regimens in a few head-to-head studies. Picard et al.9 studied genotypic resistance patterns from 42 patients given initial antiretroviral therapy combining either stavudine and didanosine or zidovudine and lamivudine for >=12 months, whose treatment failed. In contrast to our results, TAMs (i.e. T215Y mutation) occurred more frequently in the stavudine than the zidovudine group (61.9% versus 9.5%). However, this result calls for two comments: first, the patients enrolled in that study were on dual therapy and not on HAART; and secondly, in that subanalysis of the results of a randomized control trial designed to compare the efficacy of stavudine–didanosine and zidovudine–lamivudine, patients with virological failure who received the randomized treatment for <12 months were not included in the analysis. In the original analysis,10 more patients in the zidovudine–lamivudine than in the stavudine–didanosine stopped their treatment at 24 weeks (18% versus 8%). One may therefore postulate that a larger number of patients susceptible to experience resistance was excluded from the zidovudine–lamivudine group than from the stavudine–didanosine group in the subanalysis reported by Picard et al.9 Consequently, they may have underestimated resistance that occurred in the zidovudine–lamivudine group.

As regards the optimal sequencing of first-line therapy including either zidovudine or stavudine for naive patients, the higher incidence of TAMs found here among patients on first-line therapy with zidovudine than with stavudine may be an argument for starting with a combination including a stavudine backbone. However, in the present analysis, the second-line therapy including stavudine had a comparable immunological and virological outcome in patients with and without TAMs. It therefore appears that the TAMs occurring with zidovudine do not alter the subsequent response to stavudine, at least in patients who are given a potent three-drug antiretroviral regimen. Our results are consistent with those of Descamps et al.,15 who recently studied the effect of TAMs on the virological response to treatment with either zidovudine or stavudine, each combined with lamivudine and indinavir, in 155 patients previously treated with zidovudine. In that study the presence of TAMs did not prevent an early and durable virological response to an antiretroviral regimen containing either zidovudine or stavudine. However, first, our results were based on surrogate markers and we did not consider the clinical efficacy of the second-line antiretroviral regimen. Secondly, the duration of follow up in our study and that of Descamps et al. did not exceed 80 weeks. The virological and immunological efficacy of subsequent antiretroviral regimens was not studied. Avoiding TAM occurrence may be of benefit for treatments designed for longer periods.

There are several limitations to the present investigation. First, the genotypic mutation tests were not performed in all the patients who stopped their first-line therapy, because plasma samples were not always available. However, as stated in Patients and methods, we performed a sensitivity analysis in which we considered that TAMs had occurred in all patients whose plasma samples were missing. This analysis confirmed the results of our baseline analysis. Secondly, patients’ characteristics were different in the two treatment groups. Those in the stavudine group had more advanced HIV disease than those in the zidovudine group (as a higher proportion had a history of AIDS-defining events, lower CD4 cell counts and a higher viral load). This difference may have affected TAM occurrence, regardless of the antiretroviral drug used. However, because failure and consequently resistance usually occur more frequently in patients with higher viral loads and lower CD4 cell counts, TAM occurrence should have been more frequent in the patients on a stavudine- rather than a zidovudine-containing regimen, if any bias had occurred.16 On the other hand, patients with more advanced disease may be more compliant regarding their treatment and consequently have a decreased risk of viral mutations. Lastly, the drugs included in the triple regimens were not the same in the stavudine and zidovudine groups. One may therefore postulate that the lower occurrence of TAMs in the stavudine group may be due to the greater potency of the associated drugs, namely PIs, more frequently used in this group, rather than to stavudine, although whether these inhibitors are more potent than NNRTIs is still extremely controversial.

The medical literature contains few evaluations of the impact of the NRTI used in the first triple therapy on TAM occurrence. Our results suggest that TAMs occur in more patients on antiretroviral drug regimens containing zidovudine than on regimens containing stavudine. Although results derived from observational studies should be interpreted with caution, the present findings may be used in determining the optimal sequencing of zidovudine and stavudine in antiretroviral therapy for the treatment of naive HIV-infected patients. Randomized clinical trials should now be conducted to confirm these findings.


    Acknowledgements
 
We acknowledge Fanny Wojciechowski, Valérie Lambert and Françoise Taillez for their technical assistance. We are indebted to Philippe Choisy and Francis Marysse for assistance with data management. We acknowledge Stop-SIDA association for their financial support of this study.


    Footnotes
 
* Correspondence address: Centre Hospitalier Régional Universitaire, Service de Virologie-Hôpital Albert Calmette, Boulevard du Pr Jules Leclercq, 59037 Lille Cédex, France. Tel: +33-3-20-69-46-16; Fax: +33-3-20-44-69-30; E-mail: l-bocket{at}chru-lille.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Yeni, P., Hammer, S., Carpenter, C. et al. (2002). Antiretroviral treatment for adults HIV Infection in 2002. Update recommendations of the International AIDS Society—USA Panel. Journal of the American Medical Association 288, 222–34.[Abstract/Free Full Text]

2 . Delfraissy, J. F. (2002). Prise en Charge des Personnes Infectées par le VIH. Médecine-Sciences Flammarion, Paris, France.

3 . Larder, B. & Kemp, S. (1989). Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine. Science 246, 1155–8.[ISI][Medline]

4 . Kuritzkes, D., Shugarts, D., Bakhtiari, M. et al. (2000). Emergence of dual resistance to zidovudine and lamivudine in HIV-1 infected patients treated with zidovudine plus lamivudine as initial therapy. Journal of Acquired Immune Deficiency Syndromes 23, 26–34.[ISI][Medline]

5 . Gatell, J., Leal, M., Mallolas, J. et al. (1996). A pilot case-control study of zidovudine compared with zidovudine plus didanosine in patients with advanced HIV-1 disease and no previous experience with antiretrovirals. Antiviral Therapy 1, 105–12.[Medline]

6 . Yazdanpanah, Y., Chêne, G., Losina, E. et al. (2001). Incidence of primary opportunistic infections in two HIV-infected French clinical cohorts. International Journal of Epidemiology 30, 864–71.[Abstract/Free Full Text]

7 . Mouroux, M., Izopet, J., Descamps, D. et al. (2000). Conditions of selection of ‘thymidine analogue mutations’ (TAMs) in naive patients receiving different antiretroviral combinations including d4T. Pathologie-Biologie 48, 508–12.

8 . Pellegrin, I., Izopet, J., Reynes, J. et al. (1999). Emergence of zidovudine and multi-drug-resistance mutations in the HIV-1 reverse-transcriptase gene in therapy-naive patients receiving stavudine plus didanosine combination therapy. STADI Group. AIDS 13, 1705–9.[CrossRef][ISI][Medline]

9 . Picard, V., Angelini, E., Maillard, A. et al. (2001). Comparison of genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 isolates from patients treated with stavudine and didanosine or zidovudine and lamivudine. Journal of Infectious Diseases 184, 781–4.[CrossRef][ISI][Medline]

10 . Molina, J. M., Chêne, G., Ferchal, F. et al. (1999). The Albi Trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus. Journal of Infectious Diseases 180, 351–8.[CrossRef][ISI][Medline]

11 . Maguire, M., Gartland, M., Moore, S. et al. (2000). Absence of zidovudine resistance in antiretroviral-naive patients following zidovudine/lamivudine/protease inhibitor combination therapy: virological evaluation of the AVANTI 2 and AVANTI 3 studies. AIDS 14, 1195–201.[CrossRef][ISI][Medline]

12 . Sarmati, L., Nicastri, E., Parisi, S. G. et al. (2001). Failure of stavudine-lamivudine combination therapy in antiretroviral-naive patients with AZT-like HIV-1 resistance mutations. Journal of Medical Virology 65, 631–6.[CrossRef][ISI][Medline]

13 . Ross, L., Scarsella, A., Raffanti, S. et al. (2001). Thymidine analog and multinucleoside resistance mutations are associated with decreased phenotypic susceptibility to stavudine in HIV type 1 isolated from zidovudine-naive patients experiencing viremia on stavudine containing regimens. AIDS Research and Human Retroviruses 17, 1107–15.[CrossRef][ISI][Medline]

14 . Descamps, D., Flandre, P., Calvez, V. et al. (2000). Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Journal of the American Medical Association 283, 205–11.[Abstract/Free Full Text]

15 . Descamps, D., Flandre, P., Joly, V. et al. (2002). Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir. Journal of Acquired Immune Deficiency Syndromes 31, 464–71.[Medline]

16 . Haubrich, R. & Demeter, L. (2001). Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations. Journal of Acquired Immune Deficiency Syndromes 26, Suppl. 1, S51–9.[ISI][Medline]





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