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Biomedical subjects

Philippe Flandre

Publications and source records attributed to Philippe Flandre.

At least 19 recordsLinked to original sources
PubMed2006

Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients.

OBJECTIVE: To develop a clinically relevant genotypic resistance score for boosted atazanavir (ATV) in protease inhibitor-experienced patients. METHODS: At baseline, 62 patients with HIV-1 RNA > 1000 copies/ml switched to a boosted ATV regimen (300 mg ATV, 100 mg ritonavir once daily); two were excluded from analysis at 3 months as they had undetectable plasma ATV. The impact of baseline protease mutations on virological response (> 1 log10 copies/ml plasma HIV RNA decrease) at 3 months was analysed using Fisher's exact test. Mutations with prevalence > 8% and P < 0.2 were retained. Cochran-Armitage's test was used to select the combination of mutations most strongly associated with reduced virological response. Robustness of the score was investigated using bootstrap resampling. RESULTS: At 3 months, 82% of patients had a virological response and 56% had RNA < 50 copies/ml. Eight mutations (10F/I/V, 16E, 33I/F/V, 46I/L, 60E, 84V, 85V and 90M) were retained in the genotypic resistance score (P = 8.67 x 10) and virological response was observed in 100%, 100%, 80%, 42%, and 0% of patients with none, one, two, three, and four/five mutations, respectively. There was 100% response in patients with a score < 2 independently of the number of active drugs, whereas in patients with a score > or = 3 there was a gradient of response according to the number of active drugs (0%, 29% and 60% with none, one and two/three active drugs, respectively). CONCLUSIONS: The occurrence of three of the eight mutations in the ATV/RTV genotypic resistance score predicted a clinically identifiable reduced response in patients.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Quantification of the prentice criteria for surrogate endpoints.

In a recent discussion on the Prentice criteria for surrogate endpoints (1989) and the role of meta analyses in this context, Alonso et al. expand on a number of points. Among these is a suggestion to base a measure of the degree at which an endpoint meets the Prentice criteria on a likelihood reduction factor. Although new in this context, the suggestion has been studied elsewhere and the measure of Alonso et al., as presented, requires some modification if it is to be useful in general situations. As it stands it depends upon the censoring mechanism, even when independent of the failure mechanism. This is, however, easily fixed. The measure suggested by Alonso et al. can be seen to fit in with a well-established theory so that, once corrected for the presence of censoring, it can be employed with confidence. Of particular interest is the wide availability of a standard SAS program producing a coefficient which can be immediately transformed to provide an estimate of the population quantity behind the Alonso et al. proposal.

Biomarkers↗
PubMed2005

Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073).

BACKGROUND: Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs. OBJECTIVE: To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure. METHODS: Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples. RESULTS: At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations. CONCLUSIONS: In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.

Amino Acid Substitution↗
PubMed2005

Clinically relevant genotype interpretation of resistance to didanosine.

We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as -1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E - K70R - M184V/I; P = 4.5 x 10(-9)) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 x 10(-7)). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log(10) copies/ml when they were ranked as having a genotypic score II of -2, -1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.

Adult↗
PubMed2005

Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021).

Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.

Adenine↗
PubMed2005

Comparison of tests and procedures to build clinically relevant genotypic scores: application to the Jaguar study.

OBJECTIVE: To compare non-parametric tests and procedures of selection in building clinically validated genotypic scores. DESIGN AND PATIENTS: In the Jaguar study, 111 patients on a stable antiretroviral regimen experiencing virological failure were randomized in the didanosine (ddI) arm to receive ddI for 4 weeks in addition to their current combination therapy. METHODS: The virological response was HIV-1 RNA reduction from baseline to week 4. The univariate impact of each mutation associated with resistance to ddI on virological response was quantified by comparing reduction in plasma HIV-1 RNA in patients with or without the specific mutation, using a Wilcoxon-Mann-Whitney test. The next step was to select the combination of mutations most strongly associated with the virological response. Two procedures and two tests were compared using either the set of resistance mutations or the set of resistance mutations and mutations providing a better virological response. The Kruskal-Wallis and the Jonckheere test for ordered alternatives were compared in order to build a genotypic score using the two distinct procedures. RESULTS: Eight mutations were associated with a reduced virological response to ddI: M41L, D67N, T69D, L74V, V1181, L210W, T215Y/F and K219Q/E and two mutations with a better virological response: K70R and M184V/I. The Jonckheere-Terpstra test for trend provided the combination of mutations (M41L+T69D-K70R+L74V-M184V /I+T215Y/F+ K219A/E) that were the most predictive for the week 4 virological response, that is, leading to the lowest P value. The 'removing' procedure, starting from a set of mutations retained and removing mutations one by one to find the best combination, provides lower P values than the 'adding' procedure starting with a single mutation and adding mutations one by one. Whatever the set of mutations and the procedure used, the Jonckheere-Terpstra test selects combinations of mutations leading to lower P values than the Kruskal-Wallis test. CONCLUSION: The Jonckheere-Terpstra test for trend is recommended for building a genotypic score when compared with the Kruskal-Wallis. The choice of the selection procedure is discussed here and may be dependent on the objective of the score.

Anti-HIV Agents↗
PubMed2004

Estimating and comparing reduction in HIV-1 RNA in clinical trials using methods for interval censored data.

The magnitude of reduction in HIV-1 RNA levels provides an important complement to the end point based on the percentage of patients achieving HIV-1 RNA levels below a threshold value. Analyses and interpretation of this end point, however, is difficult due to the lower limit of quantification. Crude methods of analyzing HIV-1 RNA data provide biased estimates of the HIV-1 RNA reduction. Censored methods that take into account the censoring of HIV-1 RNA measurements by the limit of quantification greatly improve the analysis of HIV-1 RNA reduction end points. It was shown, however, that when there is a high percentage of censoring, those methods can overestimate HIV-1 RNA reduction. We suggest going a step further, considering that HIV-1 RNA reduction is left-censored by the limit of quantification and right-bounded by the HIV-1 RNA levels at baseline. We then suggest using nonparametric and parametric methods introduced for interval-censored data to analyze such data. A convenient feature of the methodology is the ability to easily handle missing HIV-1 RNA data, although some assumptions are required. For instance, the HIV-1 RNA reduction can be estimated using the so-called "missing = failure" scenario. Graphic procedures to check the validity of using parametric methods are described. The methods are discussed and illustrated with data of 2 recent clinical trials. Surprisingly, it was found that the log10 transformation of the HIV-1 RNA reduction was not appropriate in our data.

Clinical Trials as Topic↗
PubMed2004

A survival method to estimate the time to occurrence of mutations: an application to thymidine analogue mutations in HIV-1-infected patients.

Virologic studies of human immunodeficiency virus type 1-infected patients have investigated either the emergence of resistance mutations according to the treatment received (type I) or their effect on subsequent regimens (type II). Type I studies provide an estimation of the frequency distribution of mutations for a given duration of therapy, but the delay to emergence of these mutations cannot be assessed. We suggest using a nonparametric estimator that generalizes the Kaplan-Meier method to data from type II studies to estimate the time to occurrence of mutations. Patients had no treatment interruption before viral genotyping. Although the curves should be interpreted with caution, they provide useful information about the kinetics of the emergence of mutations. The method was applied to the emergence of thymidine analogue mutations in patients previously treated with zidovudine (ZDV) plus didanosine or zalcitabine. Although K70R has been described as the first mutation to appear in patients receiving ZDV monotherapy, the T215Y/F mutation appeared first in patients receiving dual-nucleoside combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Predictive factors and selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors according to initial regimen received.

Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219.

Anti-HIV Agents↗
PubMed2002

Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir.

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

Anti-HIV Agents↗
PubMed2002

Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial.

OBJECTIVES: To compare the incidence of clinical lipodystrophy in HIV-1-infected patients receiving zidovudine or stavudine, in combination with indinavir and lamivudine, in a randomized trial. METHODS: NOVAVIR was a randomized multicentre trial comparing stavudine/lamivudine/indinavir and zidovudine/lamivudine/indinavir in 170 patients pretreated with zidovudine, didanosine or zalcitabine (> 6 months), but naive for lamivudine, stavudine and protease inhibitors. The incidence of clinical lipodystrophy and metabolic abnormalities was assessed in a subgroup of 101 patients after 30 months of follow-up. RESULTS: The incidence of lipoatrophy was increased in the stavudine arm versus the zidovudine arm, as followed: facial atrophy: 48 versus 22% of patients, P = 0.011, lower limb atrophy: 49 versus 22% of patients, P = 0.006, buttock atrophy: 47 versus 20% of patients, P = 0.009, venomegaly: 57 versus 24% of patients, P = 0.001. There was no significant difference in the incidence of clinical signs of central fat accumulation nor in fasting metabolic parameters at month 30 between the two arms. In multivariate analyses, the stavudine arm, previous therapy with didanosine, and a lower CD4 cell count at study entry were associated with an increased risk of lipoatrophy, whereas older patients and women had an increased risk of lipohypertrophy. CONCLUSION: Patients receiving stavudine/lamivudine/indinavir had a greater rate of clinical lipodystrophy, mainly lipoatrophy, than those treated with zidovudine/lamivudine/indinavir.

Adult↗
PubMed2002

Nevirapine or lamivudine plus stavudine and indinavir: examples of 2-class versus 3-class regimens for the treatment of human immunodeficiency virus type 1.

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P<.001). Idv trough levels were 81 ng/mL in the Nvp group and 99 ng/mL in the 3TC group (P=.012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P=.013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues.

Adult↗
PubMed2002

On the use of magnitude of reduction in HIV-1 RNA in clinical trials: statistical analysis and potential biases.

Clinical trials endpoints based on magnitude of reduction in HIV-1 RNA levels provide an important complement to endpoints based on either virologic failure or a proportion of patients having HIV-1 RNA levels below a threshold value. However, reductions in HIV-1 RNA often are not completely observed, because many patients have HIV-1 RNA levels below the limit of quantification at the primary follow-up visit. The crude method of analyzing such data is to define all HIV-1 RNA levels that fall below the limit of quantification as being equal to that limit of quantification. This method is widely used even though the underestimation inherent in such a method may also lead to underestimation of treatment difference in terms of HIV-1 RNA reduction. Analyses based on Kaplan-Meier method and censored regression can be used to estimate such a reduction. When a high percentage of patients have HIV-1 RNA levels below the limit of quantification at the time of primary follow-up, which corresponds to censored observations, the Kaplan-Meier method does not always provide an estimate of the median HIV-1 RNA reduction. We discuss a statistical method to provide lower and upper limits of such median reduction or of other percentiles of reduction. We found that when the percentage of censoring is high, the censored method may overestimate the HIV-1 RNA reduction and then may also overestimate the treatment difference. Although the censored method is preferable to the crude method, when the level of censoring is high, we suggest computation of the upper and lower limits either to provide a range of potential values of HIV-1 RNA reduction or to detect overestimation by the censored method.

Anti-HIV Agents↗
PubMed2002

Final analysis of the Trilège induction-maintenance trial: results at 18 months.

BACKGROUND: First results of Trilège demonstrated that the strategy of less intensive antiviral therapy is less effective than continuation of triple-drug therapy. OBJECTIVE: To compare the final number of failures at month 18 and to study viral dynamics in patients experiencing a virological failure. DESIGN: Longitudinal follow-up from a randomized controlled trial. SETTING: Forty-three AIDS clinical-trial units. PATIENTS: A total of 279 HIV-1 infected adults randomized in Trilège. MEASUREMENTS: Analysis of recurrent values of HIV RNA > 500 copies/ml beyond time to virologic failure. RESULTS: A total of 83 patients experienced virological failure by month 18; 10 in the zidovudine (ZDV) + lamivudine (3TC) + indinavir (IDV) arm, 46 in the ZDV + 3TC arm, and 27 in the ZDV + IDV arm, confirming previous results. Whatever the treatment ultimately received, 87% of patients had an HIV RNA < 500 copies/ml at month 18 with no statistical difference between randomized arms. Patients experiencing a failure in the triple-drug regimen had a greater tendency to maintain HIV RNA > 500 copies/ml beyond the time of virological failure than patients in both less intensive treatment groups who experienced failure. Lower levels of HIV RNA at failure and reinitiating of either the original triple-drug regimen or a new combination of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors were associated with lower hazard ratios for developing recurrent HIV RNA > 500 copies/ml. CONCLUSION: Results confirmed the failure of a less intensive regimen to maintain patients with a viral suppression (HIV RNA < 500 copies/ml). Although there is a lower incidence of failure in the triple-drug regimen, randomization to a less intensive regimen of ZDV + 3TC or ZDV + IDV was not detrimental, as treatment modification, either to the original triple regimen, or a different regimen was successful.

Adult↗
PubMed2002

Kaposi's sarcoma herpesvirus and HIV-1 seroprevalences in prostitutes in Djibouti.

Kaposi's sarcoma herpesvirus (KSHV) is linked causally to Kaposi's sarcoma. Epidemiological studies have shown that KSHV transmission can occur during sex among homosexual men, but heterosexual transmission seems to be very rare in KSHV low prevalence countries. A seroepidemiological study was conducted to determine whether KSHV is transmitted sexually between heterosexuals in an endemic country. Sera from 282 subjects of African origin living in Djibouti were tested for antibodies to KSHV and HIV-1. Among the 282 individuals, 43 were female prostitutes working in the streets (group 1), 123 were female prostitutes working in luxury bars (group 2), 41 were non-prostitute females (group 3), and 75 were non-prostitute males (group 4). KSHV seroprevalence was 26, 20, 17, and 36% in groups 1, 2, 3, and 4, respectively. The seroprevalence of KSHV is not different between street or bar prostitutes and non-prostitute females (OR = 1.67; P = 0.34 and OR = 1.18; P = 0.73). These results suggest that in this endemic country commercial sex work does not seem to be a risk factor for KSHV infection and provides evidence against heterosexual transmission of KSHV in the female population studied.

Adolescent↗
PubMed2002

Efficacy of zidovudine compared to stavudine, both in combination with lamivudine and indinavir, in human immunodeficiency virus-infected nucleoside-experienced patients with no prior exposure to lamivudine, stavudine, or protease inhibitors (novavir trial).

We compared the efficacy and the toxicity of zidovudine (AZT) versus stavudine (d4T), in combination with lamivudine (3TC) and indinavir, in AZT-, dideoxyinosine (ddI)-, and/or dideoxycytosine (ddC)-experienced patients in a randomized comparative multicenter trial. One hundred seventy human immunodeficiency virus type 1 (HIV-1)-infected patients, who had received AZT, ddI, and/or ddC for at least 6 months but were naive for d4T, 3TC, and protease inhibitors, were randomized to AZT at 250 to 300 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h or to d4T at 40 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h. The primary endpoint was time to virological failure, defined as plasma HIV-1 RNA levels of >5,000 copies/ml after at least 8 weeks of antiretroviral therapy. Additional endpoints were change from baseline in CD4 cell counts, AIDS-defining events and adverse events, and proportion of patients with HIV-1 RNA levels of <500 copies/ml and HIV-1 RNA levels of <50 copies/ml. At week 80, 15 patients in the AZT arm and 14 patients in the d4T arm had reached the primary endpoint, and time to virological failure did not differ between the two arms (P = 0.98). In the d4T and in the AZT arms, 67 and 73% of patients, respectively, had HIV-1 RNA levels of <500 copies/ml (P = 0.50). The median change from baseline in CD4 cell count was 195 x 10(6) and 175 x 10(6)/liter for the d4T- and AZT-containing arms, respectively. The proportions of patients with HIV-1 RNA levels of <50 copies/ml at weeks 8, 16, and 24 were similar in the two arms. The occurrence of serious adverse events was not significantly different between arms. In conclusion, in these patients heavily pretreated with AZT, switching from AZT to d4T when initiating indinavir and 3TC did not bring any additional benefit compared to maintaining AZT.

Adult↗
PubMed2002

Adherence to antiretroviral therapy and outcomes in HIV-infected patients enrolled in an induction/maintenance randomized trial.

OBJECTIVE: To examine the effect of adherence to therapy on early virological response, later virological failure, and occurrence of adverse events in HIV-infected patients. DESIGN: A randomized trial of 3-month induction period of zidovudine/lamivudine/indinavir followed by a maintenance phase of zidovudine/lamivudine/indinavir, zidovudine/lamivudine or zidovudine/indinavir. MAIN OUTCOMES: Adherence was assessed by pill count. In the induction phase, early virological response was defined as plasma HIV-RNA<500 copies/ml at month 2 and in the maintenance phase, virological failure was defined as plasma HIV-RNA >500 copies/ml in two consecutive specimens. RESULTS: The median adherence rate was 97% in both induction (n=366) and maintenance phase (n=237). In the maintenance phase, pairwise comparisons showed a lower adherence rate in zidovudine/lamivudine/indinavir versus zidovudine/lamivudine (P=0.03), or versus zidovudine/indinavir (P=0.05). Only 13% of patients had an adherence over the maintenance phase of 80% or lower, while 40% of patients occasionally had an adherence rate of 80% or lower during this phase. Among the 362 patients with documented HIV-RNA at month 2, 86% had an early virological response. Adherence of 80% or greater was the only variable statistically predictive to early virological response (P<0.001), while baseline CD4, baseline HIV-RNA, and adherence of 95% or greater were not associated to virological response. In the maintenance phase, adherence, baseline HIV-RNA, HIV-RNA at month 3 and treatment groups were independently predictive to time to virological failure. Analysis by randomized groups indicated that difficulty in adherence (<80%) was predictive to time to failure (P<0.001) only in both indinavir-containing regimens. Occurrence of two or more severe adverse events (grade 3 and 4) was higher in patients with poor adherence although not statistically associated (P=0.12), while no association was found with minor adverse events. CONCLUSION: Adherence rate was globally lower in patients maintaining the original triple-drug therapy compared with those receiving less intensive regimens. Adherence rate was a time-dependent variable. Adherence to antiviral regimen of 80% or greater was predictive to early virological response, and adherence rate lower than 80% or 95% was predictive to virological failure, especially in indinavir-containing regimens. Occurrence of adverse events was not clearly associated to adherence.

Adult↗