Week 96 efficacy of lopinavir/ritonavir monotherapy in virologically suppressed patients with HIV: a randomized non-inferiority trial (ANRS 140 DREAM).

Background: Sparing of antiretroviral drug classes could reduce the toxicity and cost of maintenance treatment for HIV infection. Objectives: To evaluate the non-inferiority of efficacy and the safety of lopinavir/ritonavir (r) monotherapy versus a single-tablet regimen of efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) over 2 years. Methods: Adults on stable ART with plasma HIV-1 RNA viral load <50 copies/mL for the past 12 months and no documented treatment failure were randomized to receive either lopinavir/r or EFV/FTC/TDF for 2 years. The primary endpoint was the proportion of patients without treatment failure at week 96 (viral load <50 copies/mL at week 96, confirmed at week 98), without study treatment discontinuation, a new AIDS-defining illness, or death. Results: In the ITT analysis, the primary endpoint was reached by, respectively, 64% and 71% of patients in the lopinavir/r (n = 98) and EFV/FTC/TDF arms (n = 97), yielding a difference of -6.8% (lower limit of the 95% two-sided CI: -19.9%). Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2). No unexpected serious clinical events occurred. Conclusions: Lopinavir/r monotherapy cannot be considered non-inferior to EFV/FTC/TDF. PI resistance rarely emerged in the lopinavir/r arm and did not undermine future PI options. Two years of lopinavir/r monotherapy had no deleterious clinical impact when compared with EFV/FTC/TDF.

Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.

OBJECTIVES: We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). PATIENTS AND METHODS: In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. RESULTS: Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. CONCLUSIONS: In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.

Immunity, inflammation and reservoir in patients at an early stage of HIV infection on intermittent ART (ANRS 141 TIPI Trial).

OBJECTIVES: The objective of this study was to assess clinical and biological changes during intermittent ART (I-ART) started early, with significant time spent on versus off ART, which has never before been studied in ART-naive patients with high nadir and current CD4 cell count. PATIENTS AND METHODS: ART-naive HIV-1-infected patients with baseline CD4 ≥ 500/mm(3) and nadir CD4 ≥ 400/mm(3) received 2 years of I-ART (6 month periods on once-daily boosted-PI-based ART, alternating with 6 month periods without ART) in a 2 year, Phase II, non-comparative multicentre trial. The trial is registered with ClinicalTrials.gov, number NCT 00820118. RESULTS: The CD4 cell count remained ≥ 500/mm(3) at 2 years in all 44 patients included in the study. The mean 2 year count was higher than the mean count at baseline in 24 patients overall (55%; 95% CI 40%-69%) and in 20 (65%; 95% CI 48%-81%) of the 31 patients who fully adhered to the trial strategy. All but three of these latter patients had HIV-1 RNA concentrations below 50 copies/mL after each 6 month 'on' period. Only one strategy-related genotypic mutation (M184I) was detected. The HIV-1 DNA median load fluctuated, but it did not differ between month 0 and month 24 (2.8 versus 2.6 log10 copies/10(6) leucocytes, P = 0.29). Biomarkers of inflammation and endothelial activation remained stable between month 0 and month 24. Naive CD4, CD8+CCR5+ and CD8+CD38+ T cell numbers tended to decline. One patient developed Burkitt's lymphoma and 12 patients reported sexually transmitted infections. CONCLUSIONS: In patients with high nadir and current CD4 cell counts, 2 year I-ART maintained the CD4 cell count above 500/mm(3), with no increase in the viral reservoir. Immune activation seems related to HIV replication, while inflammation seems to evolve independently and require specific attention.

Drug resistance and tropism as markers of the dynamics of HIV-1 DNA quasispecies in blood cells of heavily pretreated patients who achieved sustained virological suppression.

OBJECTIVES: The objective of this study was to address the dynamics of archived resistant quasispecies in cell-associated HIV-1 DNA over time in heavily ART-experienced patients with currently suppressed plasma HIV-1 RNA. METHODS: Longitudinal ultra-deep sequencing (UDS) analysis of reverse transcriptase, protease and V3 Env regions was performed on blood-cell-associated HIV-1 DNA samples. Drug-resistance-associated mutations (DRAMs) and tropism were interpreted using the ANRS and Geno2Pheno algorithms. We analysed frozen blood cells from patients enrolled in the INNOVE and ANRS 123 ETOILE studies who achieved sustained viral suppression after salvage optimized ART (SOT). RESULTS: Samples were available at baseline and 6 and ≥12 months after SOT initiation in 10 patients. V3 loop sequences displayed wide intra-individual dynamics over time. Viral variants harbouring DRAMs exhibited three non-exclusive scenarios. First, when SOT exerted the same selective pressure as previous failing regimens, some viral quasispecies still harboured the same DRAMs at the same level as at the time of virological failure. Thus, as DRAMs were mostly associated with the same viral variant, variants with a complete resistance pattern remained archived. Second, some viral variants harbouring DRAMs were no longer detected over time when SOT consisted of new antiretroviral classes or had resistance profiles distinct from those of previous failing regimens. Third, variants with new DRAMs associated with SOT emerged in blood cells during follow-up despite sustained virological control. CONCLUSIONS: Using longitudinal UDS analysis and focusing on DRAMs and tropism as markers, we demonstrated that, despite sustained virological control, archived HIV-1 DNA quasispecies continued to evolve.

Tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients treated for tuberculosis: the ANRS 129 BKVIR trial.

BACKGROUND: HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens. METHODS: The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks. RESULTS: TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02). CONCLUSION: These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB.

Pharmacokinetics of Raltegravir in HIV-Infected Patients on Rifampicin-Based Antitubercular Therapy.

BACKGROUND: Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human immunodeficiency virus (HIV)-infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial. METHODS: Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3). RESULTS: In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for the 12-hour area under the time-concentration curve (AUC0-12), and 0.69 (90% CI, .42-1.13) for the concentration at 12 hours (C12). In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3. CONCLUSIONS: The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC0-12 and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection. CLINICAL TRIALS REGISTRATION: NCT0082231.

Highly frequent HIV-1 minority resistant variants at baseline of the ANRS 139 TRIO trial had a limited impact on virological response.

OBJECTIVES: To assess the prevalence of minority resistant variants (MRVs) at baseline and their impact on the virological response. The ANRS 139 TRIO trial evaluated the combination of raltegravir, etravirine and darunavir, plus an optimized background therapy, in 87% of cases. Patients were highly experienced and harboured multiresistant viruses, but were naive to the three drugs, and showed a high level of virological suppression. METHODS: Ultra-deep sequencing of reverse transcriptase, protease and integrase regions was performed at the trial baseline, and sequences were interpreted according to the ANRS algorithm. MRVs were assessed using MiSeq and 454 technologies (limit of detection 1%). RESULTS: At baseline, minority variants with at least one NRTI, one NNRTI, one PI, one major PI or an integrase inhibitor resistance-associated mutation were present in 46%, 45%, 68%, 24% and 13% of patients, respectively. When minority variants are taken into account, the prevalence of resistance to etravirine, darunavir and raltegravir at baseline was 29%, 40% and 9%, respectively. No difference was observed in the prevalence of MRVs between patients with virological failure and those with virological success, except a trend for patients exhibiting baseline etravirine MRVs (50% versus 26%, P = 0.09). CONCLUSIONS: We have shown a high level of MRVs at baseline in highly pre-treated patients harbouring multiresistant viruses. However, these MRVs were not associated with an increased risk of virological failure, except for a trend for etravirine MRVs.

Characterization of binding of raltegravir to plasma proteins.

The objective of this study was to characterize raltegravir (RAL) binding to albumin and alpha-1-acid glycoprotein (AAG). Unbound and bound RAL were separated by ultrafiltration. The association constant (Ka) was estimated by a graphical method. In HIV-infected patients, the average plasma protein binding is 76%. RAL did not bind to AAG but bound to nonsaturable, low-affinity albumin sites with an n (number of sites) · Ka product of 9.8 × 10(2) liters/mol. A pH increase of 0.2 U led to a 2% increase in the bound fraction.

Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo).

We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

Role and evolution of viral tropism in patients with advanced HIV disease receiving intensified initial regimen in the ANRS 130 APOLLO trial.

OBJECTIVES: The aims of the study were to assess in patients with advanced HIV disease receiving antiretroviral therapy (ART) intensification with enfuvirtide (i) resistance at virological failure (VF), (ii) impact of baseline tropism on immunovirological response, and (iii) HIV-1 DNA tropism evolution during ART. METHODS: The ANRS 130 APOLLO randomized trial evaluated in naive patients the immunovirological impact of standard ART without (control arm) or with enfuvirtide. Tropism was determined on RNA and DNA by V3-loop sequencing interpreted using the Geno2Pheno algorithm. RESULTS: At baseline the median CD4 cell count was 30 cells/mm(3). Among the 170 patients assessable in this virological substudy, HIV-1 RNA tropism was as follows: 60% of viruses were R5 and 40% were R5X4/X4. HIV-1 DNA tropism was as follows: 54% were R5 and 46% were R5X4/X4. At week 24, 39% and 49% of patients experienced VF in the enfuvirtide and control arms, respectively. In the enfuvirtide arm, only resistance-associated mutations to enfuvirtide were detected. In the control arm, two patients displayed drug-resistant viruses at the time of VF. No impact of baseline tropism was observed on immunovirological response, regardless of the study arm. Among the 25 patients experiencing DNA tropism switch between baseline and week 24, 16 (64%) switched from R5 to R5X4/X4. These latter were mostly successfully suppressed patients receiving enfuvirtide and exhibiting poorer immunological response. CONCLUSIONS: Baseline RNA tropism had no impact on the immunovirological response. Drug resistance mutations were only detected for the fusion inhibitor. Finally, the mechanism of replenishment of the viral cellular reservoir with X4 viruses observed needs to be further analysed.

Preserving participant anonymity during remote preenrollment consent form checking.

BACKGROUND: In biomedical research, the consent form must comply with regulatory requirements. Checking for compliance typically has been performed on-site and most frequently after a participant's final enrollment. We use a procedure for remote preenrollment checking of consent forms that protects participant identities. This procedure requires a copy of the consent form that partially masks the fields for participant's name and signature; this copy is faxed to the clinical trials unit for checking. PURPOSE: To describe our efforts to identify an appropriate printed masking pattern. We tried several patterns that permit ascertainment of the presence of signatures and names and evaluated each one with respect to degree of masking participant identities. METHODS: We assessed the efficiency of a satisfactory pattern through an experiment. We created forms with variants of the masking pattern on the copy to be faxed. We completed the forms with fictitious identities before copies were faxed and checked by clinical research associates. We measured the rate of empty and filled fields detected and the rate of letters and names correctly read. The target was defined as 100% for the rate of empty and filled fields detected and 0% for the rate of letters and names correctly read. RESULTS: The best masking pattern allowed the detection of 100% empty and filled fields and the reading of 0% names and 19% letters. Consequently, the consent form with the selected masking pattern has been used routinely in our clinical trials unit. LIMITATIONS: We tested only five fictitious identities, five individuals who completed forms, and three who checked forms. Also, we initially considered only four patterns and variations in them. CONCLUSIONS: We defined a masking pattern that satisfactorily fulfilled our needs for confidentiality. This and other procedures for remote preenrollment checking of consent form can be a key component of a risk-based monitoring strategy.

Higher HIV-1 DNA associated with lower gains in CD4 cell count among patients with advanced therapeutic failure receiving optimized treatment (ANRS 123--ETOILE).

OBJECTIVE: To describe HIV-1 DNA levels from baseline (W0) to week 52 (W52) among patients receiving either interleukin-2 (IL-2) + optimized background therapy (OBT) or OBT as salvage treatment. METHODS: This was evaluated in a substudy of the ETOILE Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) 123 trial (patients with CD4 ≤ 200/mm(3), HIV RNA>4 log(10) copies/mL and a genotypic score showing two or fewer active drugs). OBT included enfuvirtide whenever possible. HIV DNA was quantified with the ANRS assay. RESULTS: Blood samples were available for 21 patients in the IL-2 + OBT arm and 23 in the OBT alone arm at baseline, and for 10 and 17 patients, respectively, at W52. Median baseline CD4 count was 47 cells/mm(3) and 68 cells/mm(3), respectively; median HIV RNA was 5.1 and 4.9 log(10) copies/mL. Baseline median HIV DNA load was 3.44 log(10) copies/10(6) peripheral blood mononuclear cells (PBMCs) (interquartile range 3.31-4.08) and 3.51 (3.18-3.82) log(10) copies/10(6) PBMCs, respectively. At W52, it was 3.18 log(10) copies/10(6) PBMCs (2.75-3.52) and 3.48 log(10) copies/10(6) PBMCs (3.10-3.67), respectively. Cells were available at both W0 and W52 for 7 patients in the IL-2 + OBT arm and 14 in the OBT arm. Change in HIV DNA load was not associated with IL-2 use, but decreased among the seven patients receiving enfuvirtide (-0.22 log(10) copies/mL) as compared with the other 14 patients (+0.20 log(10); P=0.046). A steeper decrease in HIV DNA was observed among patients who had a larger increase in CD4 count (Pearson coefficient ρ=0.659, P=0.001). Adjusted for enfuvirtide use, there was a trend for an association between upper baseline HIV DNA level and a less frequent CD4 gain ≥ 50 cells/mm(3) at W52 (odds ratio=0.17, P=0.075). CONCLUSIONS: HIV DNA levels were high in patients with advanced therapeutic failure. A larger viral reservoir may be associated with lower gains in CD4 count among patients receiving OBT. HIV DNA level could be a useful tool for the case management of patients in the late stages of disease.

Virological and immunological response in HIV-1-infected patients with multiple treatment failures receiving raltegravir and optimized background therapy, ANRS CO3 Aquitaine Cohort.

BACKGROUND: The efficacy of raltegravir plus optimized background therapy (OBT) has been demonstrated for antiretroviral (ARV)-experienced HIV-1-infected patients in randomized clinical trials. We studied viro-immunological response, pharmacokinetic parameters and genotypic test results in an observational cohort of multiple ARV class-experienced patients starting a raltegravir-based regimen. METHODS: Already enrolled ANRS CO3 Aquitaine Cohort patients with virological failure were included in this study after starting a raltegravir-based regimen (400 mg twice a day, week 0). Virological success was defined by the plasma HIV-1 RNA level [viral load (VL)] <2.7 log(10) copies/mL at week 12 and <1.7 log(10) copies/mL at week 24. One patient was excluded from further analysis (no follow-up after week 4). RESULTS: Fifty-one patients [male/female = 43/8, median age = 48 (interquartile range = 43, 55) years] were included. At week 0, median CD4 count was 244 (110; 310)/mm(3) and median VL was 4.2 (3.6, 4.7) log(10) copies/mL. At week 24, 39 (78%) patients experienced virological success: 4 (44%), 14 (82%) and 21 (87%) patients with a genotypic sensitivity score <1, > or =1 and <2 and > or =2 (P = 0.02), respectively. Raltegravir-related mutations emerged in 9 of 11 failing patients (82%): Q148H/R (n = 5), N155S/H (n = 3) and S230N (n = 1). Median CD4 increases from week 0 to week 4 and week 24 were 28 (-4, 85) and 57 (0, 156) cells/mm(3), respectively. A poor immune response was independently associated with a lower VL decline (week 0 to week 12) [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.4, 8.4, for 1 log(10) less] and CD4+% at baseline (OR: 2.6, 95% CI: 0.97, 8.3, for 10% lower). CONCLUSIONS: Raltegravir plus OBT provided a good virological success rate in highly pre-treated patients under clinical routine conditions.

Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial.

BACKGROUND: Tobacco smoking is common in people living with HIV, but high-quality evidence on interventions for smoking cessation is not available in this population. We aimed to assess the efficacy and safety of varenicline with counselling to aid smoking cessation in people living with HIV. METHODS: The ANRS 144 Inter-ACTIV randomised, parallel, double-blind, multicentre, placebo-controlled phase 3 trial was done at 30 clinical hospital sites in France. People living with HIV who had smoked at least ten cigarettes per day for 1 year or longer, were motivated to stop smoking, were not dependent on another psychoactive substance, and had no history of depression or suicide attempt were eligible. Using a computer-generated randomisation sequence, we allocated (1:1) the patients to receive either varenicline titrated to two 0·5 mg doses twice daily or placebo twice daily for 12 weeks, plus face-to-face counselling. Patients and investigators were masked to treatment group allocation. Patients who were not abstinent at week 24 were offered open-label varenicline for 12 additional weeks. The primary outcome was the proportion of smokers continuously abstinent from week 9 to week 48. Smoking status was confirmed by carbon monoxide in exhaled air. Primary analyses were done in both the intention-to-treat (ITT) population and modified ITT (mITT) population, which comprised all patients who took at least one tablet of their assigned study treatment. The safety analyses were done in the mITT population. The trial is registered at ClinicalTrials.gov, number NCT00918307. The trial status is complete. FINDINGS: From Oct 26, 2009, to Dec 20, 2012, of 303 patients assessed for eligibility, 248 patients were randomly assigned to the varenicline group (n=123) or the placebo group (n=125). After randomisation, one participant initially assigned to the placebo group was excluded from the ITT analysis for a regulatory reason (no French health-care coverage). 102 patients in the varenicline group and 111 patients in the placebo group received at least one dose of their assigned treatment and were included in the mITT analysis. In the ITT analysis, varenicline was associated with a higher proportion of patients achieving continuous abstinence over the study period (week 9-48): 18 (15%, 95% CI 8-21) of 123 in the varenicline group versus eight (6%, 2-11) of 124 in the placebo group, adjusted odds ratio (OR) 2·5 (95% CI 1·0-6·1; p=0·041). In the mITT analysis, varenicline was also associated with higher continuous abstinence: 18 (18%, 95% CI 10-25) of 102 versus eight (7%, 2-12) of 111 in the placebo group (adjusted OR 2·7, 95% CI 1·1-6·5; p=0·029). The incidence of depression was 2·4 per 100 person-years (95% CI 0·6-9·5; two [2%] of 102) in the varenicline group and 12·4 per 100 person-years (95% CI 6·9-22·5; 11 [10%] of 111) in the placebo group. 14 (7%) of 213 participants had 18 cardiovascular events: six (6%) of 102 people in the varenicline group and eight (7%) of 111 people in the placebo group. INTERPRETATION: Varenicline is safe and efficacious for smoking cessation in people living with HIV and should be recommended as the standard of care. FUNDING: The French National Institute for Health and Medical Research (INSERM)-French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Pfizer.

Biphasic decline of CD4 cell count during scheduled treatment interruptions.

In 115 patients whose scheduled treatment interruptions (STI) lasted 24 weeks, the CD4 cell count declined by a median of 30 cells/ml/week during the first 4 weeks, compared with 3 cells/ml/week during the next 20 weeks. In multivariate regression, a pronounced early fall in CD4 cells correlated with a higher CD4 cell count at the start of STI, with more gain in CD4 cells during antiretroviral treatment preceding STI, and with a higher viral load at week 4.

A prospective trial of structured treatment interruptions in human immunodeficiency virus infection.

BACKGROUND: According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead to low viremia after withdrawal of highly active antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease course than is currently recommended would like to discontinue, but it is unknown whether it is safe to do so. OBJECTIVES: To determine whether repeated treatment interruptions of HAART (1) stimulated the cytotoxic HIV-specific immune response and whether such stimulation correlated with low viremia off treatment, and (2) were safe with respect to clinical complications, development of viral resistance, and decline in CD4 cell counts. DESIGN: Interventional study with before-after comparison. SETTING: Outpatient clinics of university hospitals in Switzerland and Spain. PATIENTS: A total of 133 patients receiving HAART, with a median CD4 cell count of 740/ microL, and whose viral load had been undetectable for a median of 21 months. INTERVENTIONS: HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After 4 such cycles, treatment was indefinitely suspended 40 weeks after study entry. MAIN OUTCOME MEASURES: HIV-specific cytotoxic T-cell responses were evaluated by interferon gamma enzyme-linked immunospot analysis. The proportion of "responders" (viral load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and CD4 cell counts were recorded. RESULTS: Seventeen percent of patients (95% confidence interval, 11%-25%) were responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased between week 0 (median, 343 spot-forming cells per million peripheral blood lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there was an inverse correlation between response and the number of spot-forming cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and 55 (41%) for at least 56 weeks. The median CD4 cell count decreased from 792/ microL to 615/ microL during the first 12 weeks without treatment, but stabilized thereafter. One patient (0.75%) developed drug resistance necessitating salvage treatment. There were no AIDS-related clinical complications. CONCLUSIONS: Results of this study do not favor the autovaccination hypothesis. Treatment interruptions did not provoke clinical complications, and there was little drug resistance. Comparative trials will have to show what benefit, if any, is associated with intermittent, as opposed to continuous treatment.

Recent developments in clinical trial designs for HIV vaccine research.

HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development.

Tropism distribution among antiretroviral-naive HIV-2-infected patients.

The aim of this study was to describe HIV-2 R5/X4-tropism distribution in antiretroviral-naive HIV-2-infected patients. Population sequencing of the gp105 region was performed on peripheral blood mononuclear cells issued from 151 antiretroviral-naive patients. Tropism was successfully determined in 46 of 151 samples (30%) with six of 46 (13%) X4-tropic viruses. X4-tropism was associated with lower CD4 cell count (337 vs. 551/mm; P = 0.032) but not with plasma viral load. Thus, X4-tropism prevalence in HIV-2 antiretroviral-naive patients is similar to that observed in HIV-1.

Proviral HIV-DNA predicts viral rebound and viral setpoint after structured treatment interruptions.

In HIV-1-infected patients with long-term undetectable viraemia on highly active antiretroviral treatment (HAART), we found that pre-HAART plasma viraemia and the baseline proviral DNA level were significantly associated with the viraemia setpoint during scheduled treatment interruptions. In long-term treated patients, pre-HAART viraemia may not be available, and in these circumstances proviral DNA, measured at the time of scheduled treatment interruption, can help to identify patients likely to reach a low viraemia setpoint after treatment interruption.

A controlled trial of granulocyte macrophage-colony stimulating factor during interruption of HAART.

OBJECTIVES: To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART). METHODS: Patients on effective HAART (CD4 cell count > 400 x 10(6)/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks' scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored. RESULTS: Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 x 10(6) cells/l; P < 0.001); there was no such tendency in the GM-CSF group (P = non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257), P = 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections. CONCLUSIONS: The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.