Philippe Flandre

A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients

BACKGROUND The long-term effectiveness of potent three-drug antiretroviral regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection is limited by problems related to compliance and tolerability. We investigated whether two-drug maintenance therapy would suppress viral replication after a three-month period of aggressive triple-drug induction therapy. METHODS A total of 378 HIV-1-infected adults who had not received previous antiretroviral treatment received three months of induction therapy consisting of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 800 mg of indinavir every 8 hours. The 279 patients in whom the plasma HIV-1 RNA titer fell below 500 copies per milliliter after two months of triple-drug therapy, and who completed the induction phase, were randomly assigned at month 3 to one of the following three open-label maintenance regimens: zidovudine, lamivudine, and indinavir; zidovudine and lamivudine; or zidovudine and indinavir. The primary end point was an increase in HIV-1 RNA levels to 500 copies or more per milliliter during the maintenance phase. RESULTS The proportion of patients who reached the primary end point was significantly higher among patients receiving zidovudine plus lamivudine (29 of 93 patients, P<0.001) or zidovudine plus indinavir (21 of 94, P=0.01) than among patients receiving continued triple-drug therapy (8 of 92). This higher failure rate in the groups treated with the two-drug maintenance regimens was also observed in the subgroup of patients with maximally suppressed HIV-1 RNA (below 50 copies per milliliter) at the time of randomization to maintenance therapy. CONCLUSIONS In HIV-1-infected adults not previously treated with antiretroviral drugs whose plasma HIV-1 RNA levels fell below 500 copies per milliliter after three months of induction therapy with zidovudine, lamivudine, and indinavir, two-drug maintenance therapy was less effective in sustaining a reduced viral load than continued three-drug therapy.

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.

Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients.

Background:Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options. Methods:MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100 000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48. Results:Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment. Conclusion:Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.

Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136.

Background:Darunavir/ritonavir (darunavir/r) maintenance strategy, in patients with suppressed HIV RNA viremia, is a potential long-term strategy to avoid nucleoside analogue toxicities and to reduce costs. Methods:MONOtherapy Inhibitor protease is a prospective, open-label, noninferiority, 96-week safety and efficacy trial in virologically suppressed patients on triple therapy who were randomized to a darunavir/r triple drug regimen or darunavir/r monotherapy. The primary endpoint was the proportion of patients with HIV RNA less than 400 copies/ml at week 48; treatment failure was defined as two consecutive HIV RNA more than 400 copies/ml (time to loss of virologic response) or any change in treatment. The trial had 80% power to show noninferiority for the monotherapy arm (δ=−10%, 90% confidence interval). Results:A total of 242 patients were screened, 225 of whom were randomized. In the per protocol efficacy analysis, treatment success was 99% on darunavir/r triple drug versus 94% on darunavir/r monotherapy (δ = −4.9%, 90% confidence interval, from −9.1 to −0.8). Similar results were found in intent-to-treat population (92 versus 87.5%, δ = −4.5%, 90% confidence interval from −11.2 to 2.1). Three patients experienced virologic failure on darunavir/monotherapy and none on darunavir/r triple drug. No resistance to protease inhibitor emerged in patients with plasma viral load above 50 copies/ml. The two groups did not differ in the number of serious adverse events. Conclusion:Darunavir/r monotherapy exhibited efficacy rate over 85% with concordant results in the magnitude of difference with darunavir/r triple drug regimen in both intent-to-treat and per protocol analyses, but discordant conclusions with respect to the noninferiority margin. Patients failing on darunavir/r monotherapy had no emergence of new darunavir resistance mutations preserving future treatment options.

Evaluation of the Genotypic Prediction of HIV-1 Coreceptor Use versus a Phenotypic Assay and Correlation with the Virological Response to Maraviroc: the ANRS GenoTropism Study

ABSTRACT Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.

Clinically Relevant Genotype Interpretation of Resistance to Didanosine

ABSTRACT 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 × 10−9) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 × 10−7). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log10 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.

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 Fishers exact test. Mutations with prevalence > 8% and P < 0.2 were retained. Cochran–Armitages 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 × 10−9) 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 ≥ 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.

Increasing prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-infected patients from 2001 to 2006/2007 in France

OBJECTIVES To estimate the prevalence of transmitted drug resistance mutations and non-B subtype circulation in antiretroviral-naive chronically HIV-1-infected patients in France. METHODS Resistance mutations were sought in samples from 530 newly diagnosed HIV-1-infected patients from October 2006 to March 2007. Protease and reverse transcriptase mutations were identified from the 2007 Stanford Resistance Surveillance list. RESULTS Reverse transcriptase and protease resistance mutations were determined in 466 patients with duration of seropositivity <5 years. 42% of patients were infected with non-B subtype strains (CRF02 18.3%). The overall prevalence of viruses with protease or reverse transcriptase mutations was 10.6% (95% confidence interval 6.7-16.3). The prevalence of protease inhibitor, nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor resistance-associated mutations was 4.7%, 5.8% and 2.8%, respectively. Frequency of resistance was not different in patients infected with B (9.5%) and non-B (CRF02 7.8% and other 11.2%) subtypes. Baseline characteristics such as gender, age, transmission group, country of transmission, disease stage, CD4 counts and viral load were not associated with the prevalence of transmitted drug resistance. CONCLUSIONS In France in 2006/2007, the prevalence of transmitted drug-resistant variants was 10.6%. Prevalence of transmitted drug resistance was comparable in B and non-B subtypes. Prevalence of non-B subtypes is still rising.

Factors Associated With Virological Failure in HIV-1–Infected Patients Receiving Darunavir/Ritonavir Monotherapy

BACKGROUND Our objective was to determine virological and clinical characteristics associated with virological failure in human immunodeficiency virus (HIV)-infected patients switching to darunavir/ritonavir (DRV/r) monotherapy. METHODS The main outcome was virologic rebound, defined as 2 consecutive measurements of HIV-1 plasma RNA viral load (VL) >50 copies/mL. A logistic model was used to investigate which variables were predictive of a virologic rebound at weeks 48 (W48) and 96 (W96). RESULTS Receiving DRV/r monotherapy was associated with virologic rebound at W48 (P = .016) and W96 (P = .002), comparable to triple therapy. In the DRV/r monotherapy group, at W48, having a VL >50 copies/mL at day 0 and even a baseline ultrasensitive VL >1 copy/mL were predictive factors to virologic rebound (P = .042 and P = .025, respectively). At W96, shorter time of prior antiretrovial therapy (ART) exposure (odds ratio [OR] = 2.93 per 5 years decrease; P = .006), higher HIV-1 DNA at day 0 (OR = 2.66 per 1 log(10) copies/10(6) cells increase; P = .04) and adherence <100% (OR = 3.84 vs 100%; P = .02) were associated with an increased risk of rebound. CONCLUSIONS Factors associated with virological failure in patients receiving DRV/r monotherapy were having an initial blip, shorter time of antiretroviral treatment before monotherapy, and an adherence <100% during monotherapy. The importance of prior duration exposure to ART was in agreement with the impact of HIV-1 blood reservoir and VL level at baseline.

Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma on a 2002-2011 survey.

Objectives:To estimate the frequency of detectable seminal HIV-1 viral load in men with repeatedly undetectable blood viral load, in the recent past years and over a 10-year period (2002–2011) in a large cohort of HIV-1-infected men from couples requesting assisted reproduction technologies. We also searched for an association between HIV-1 RNA seminal viral load, HIV-1 RNA plasma viral load measured by ultrasensitive assay, and blood HIV-1 DNA in a subgroup of 98 patients. Methods:Three hundred and four HIV-1 infected men have provided 628 paired blood and semen samples. In a subset of 98 patients for which a blood sample was available, residual viremia, HIV-1 RNA in semen and HIV-1 DNA were studied. Results:Twenty of 304 patients (6.6%) had detectable HIV-1 RNA in semen, ranging from 135 to 2365 copies/ml, corresponding to 23 samples, although they had concomitantly undetectable HIV-1 RNA in blood while they were under antiretroviral therapy. This prevalence was stable over time even in recent years. There was an association between HIV-1 RNA plasma viral load measured by ultrasensitive assay and HIV-1 DNA in blood, but both were not associated with seminal HIV-1 RNA viral load. Conclusion:It seems cautious individually to maintain the recommendations of safe sex and the recourse to ART, or at least to inform the couple of the residual potential risk, in serodiscordant couples desiring a child.