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Introduction People who inject drugs represent an under-treated chronic hepatitis C virus (HCV)-infected patient population. Methods INTEGRATE was a prospective, observational study investigating the effectiveness, safety, and adherence in routine clinical practice to telaprevir in combination with peg-interferon and ribavirin (Peg-IFN/RBV) in patients with history of injecting drug use chronically infected with genotype 1 HCV. Results A total of 46 patients were enrolled and included in the intent-to-treat (ITT) population. Among heroin and/or cocaine users (n = 37; 80%), 22% reported use in the past month; 74% (34/46) of patients were on opioid substitution therapy in the pre-treatment phase, and 43% (20/46) discontinued HCV treatment prematurely. Sustained virologic response rate was 54% (25/46) in the ITT population and 74% (25/34) in the per protocol (evaluable-for-effectiveness) population. The main reason for failure in the ITT analysis was loss to follow-up (n = 8; 17%). Adverse events occurred in 91% (42/46) of patients. Mean patient-reported adherence to study drugs was >89% at Week 4, Week 12 and end of treatment. Conclusion Despite a high rate of treatment discontinuation (including loss to follow-up), self-reported adherence to treatment was good and virologic cure rates were similar to those reported in large real-world cohorts. Our findings suggest that people with a history of injecting drug use should be considered for treatment of chronic HCV infection, and highlight the need for improvements in patient support to boost retention in care and, in turn, help to prevent reinfection and transmission. Clinical trial registration Clinicaltrials.gov identifier, NCT01980290. Funding Janssen Pharmaceuticals.

Background & Aims: We investigated the efficacy and safety of simeprevir plus daclatasvir in treatment-naïve patients with chronic, genotype 1b hepatitis C virus infection and advanced liver disease, excluding patients with pre-defined NS5A resistance-associated substitutions. Methods: This phase II, open-label, single-arm, multicentre study included patients aged≥18years with advanced fibrosis or compensated cirrhosis (METAVIR F3/4). Patients with NS5A-Y93H or L31M/V resistance-associated substitutions at screening were excluded. Simeprevir (150mg)+daclatasvir (60mg) once daily was administered for 12 or 24weeks; treatment could be extended to 24 weeks prior to or at the Week 12 visit. Primary efficacy endpoint was sustained virological response 12weeks after the end of treatment. Results: A total of 106 patients were treated; 27% patients were aged >65years, 39% had cirrhosis, 53% had estimated glomerular filtration rate 30-89mL/min, 14% had diabetes, and 38% had arterial hypertension. Overall, 42/106 received 12weeks of treatment and 64/106 received 24weeks of treatment. Ninety-seven (92%) patients achieved a sustained virological response 12 weeks after the end of treatment. The reasons for failure were viral breakthrough (n=7) at weeks 4-16, early treatment discontinuation (n=1) and viral relapse (n=1). Seventy-four (70%) patients had ≥1 adverse event during treatment, including six (6%) patients with ≥1 serious adverse event. Three (3%) patients discontinued treatment owing to adverse events. Conclusions: Simeprevir+daclatasvir demonstrated strong antiviral activity and was well-tolerated in patients with hepatitis C virus genotype 1b infection, advanced liver disease and a high prevalence of comorbidities. However, viral breakthrough occurred in seven patients, making this regimen unsatisfactory.

Background & Aims Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. Methods Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. Results Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13–3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52–2.93), HCV genotype (OR = 0.58; 95% CI, 0.36–0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40–0.97). Conclusions Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.

Objectives: HPC3005 is a multicentre, open-label, telaprevir trial in HCV/HIV coinfected patients with severe fibrosis or compensated cirrhosis. Methods: Patients were treated with telaprevir 750 mg every 8 h (1125 mg if on efavirenz) plus pegylated interferon-alpha (PEG-IFN, 180 μg once-weekly) and ribavirin (RBV, 800 mg/day) for 12 weeks, followed by 36 weeks of PEG-IFN/RBV. Results: Mean age was 44 years, 97/118 patients were male and all were Caucasian, 68 had severe fibrosis and 50 had cirrhosis. Seventy-eight had HCV RNA levels ≥800 000 IU/mL, 72 had HCV genotype 1a, baseline HIV RNA was

Background The phase 3 studies of telaprevir (T) in combination with peginterferon α-2a and ribavirin (PR) in treatment-naive genotype 1 chronic hepatitis C virus-infected patients (ADVANCE/ILLUMINATE) were not designed a priori to assess the effect of race and ethnicity on treatment response. However, these factors are important given the lower sustained virologic response (SVR) rates observed in black and Hispanic/Latino patients treated with PR. Goals This retrospective pooled analysis evaluated the effect of race or ethnicity on treatment-naive patient response to telaprevir-based therapy and assessed resistant variant profiles. Materials and methods This analysis comprised patients enrolled in ADVANCE (N=363) and ILLUMINATE (N=540) who received 12 weeks of telaprevir in combination with PR followed by 12 or 36 weeks of PR alone and patients in ADVANCE (N=361) who received 48 weeks of PR alone. Race and ethnicity were self-reported and not mutually exclusive. Results Higher SVR rates were observed with telaprevir-based therapy compared with PR in blacks [n=99 (62%) vs. n=28 (29%), respectively] and in Hispanics/Latinos [n=89 (72%) vs. n=38 (39%)]. The SVR was lower in telaprevir-treated blacks [n=99 (62%)] compared with nonblacks [n=791 (78%)] and in Hispanic/Latinos compared with non-Hispanics/Latinos [n=89 (72%) vs. n=801 (76%)]. Low discontinuation rates due to adverse events, including rash and anemia, were observed across subgroups. Resistance profiles were similar among the subgroups. Conclusions Treatment-naive black and Hispanic/Latino patients with genotype 1 chronic hepatitis C virus infection may benefit from telaprevir-based therapy, an important finding given the lower SVR rates observed in these patients when they are treated with PR alone.

Background Monitoring ribavirin concentrations during hepatitis C treatment with dual therapy can help optimize treatment response and minimize anaemia. A defined therapeutic range for ribavirin during direct-acting antiviral-based therapies is lacking. This analysis explores whether a therapeutic range for ribavirin concentrations can be defined in patients treated with boceprevir- or telaprevir-based triple therapies. Methods Treatment-naive patients from ADVANCE, ILLUMINATE, OPTIMIZE and SPRINT-2, and treatment-experienced patients from RESPOND-2 were included. Multivariable logistic regression analyses were performed to evaluate whether ribavirin concentrations were an independent predictor of sustained virological response or anaemia. Optimal cutoff values and the percentage of patients within the proposed therapeutic range were determined, along with the associated chance of response. Results Overall, 1,502 patients were included. In both regimens, ribavirin concentrations were significantly associated with anaemia (haemoglobin level Conclusions We established the therapeutic range for ribavirin in boceprevir- and telaprevir-based therapy that balances safety and efficacy.

There is little information regarding the extent to which difficult to cure patients with advanced liver fibrosis, due to hepatitis C virus genotype-1 (HCV-1) can successfully and safely be treated with triple therapy with telaprevir (TVR), pegylated interferon alpha (P) and ribavirin (R). In the TVR early access program HEP3002 we aimed to explore treatment safety and efficacy, and identify predictors of sustained virological response at week 24 (SVR24).1078 patients with bridging fibrosis (n=552) or cirrhosis (n=526) diagnosed by either liver biopsy or non-invasive markers, with compensated bone marrow (neutrophils1500/mm(3), Hb12/13 g/dl) and liver function (Albumin3.3g/dl, Platelets90,000/ml) received TVR PR for 12 weeks, followed by a PR tail according to label.Overall, 614 (57%) achieved SVR24 by intention-to-treat analysis. The SVR24 rate was 68% in 221 treatment naïve patients (62.8% F4), 72% in 356 prior relapsers (64.4% F4), 55% in 139 partial responders (53.2% F4), and 34% in 294 null responders (28.6% F4). The SVR24 rate to response-guided therapy (24 weeks treatment duration if undetectable viremia at weeks 4 and 12) was 84% in 222 naïve/relapser F3 patients. Independent predictors of response were: (A) F3 (odds ratio (OR)=1.51, 95% CI 1.31-2.00, p=0.005), (B) subtype 1b (OR=1.63, 95% CI 1.18-2.24, p=0.0029), (C) alpha-fetoprotein10 ng/ml (OR=2.50, 95% CI 1.87-3.36, p0.0001) and (D) any prior response other than null (OR=3.29, 95% CI 2.40-4.52, p0.0001). SVR24 rose for patients who had more of these predictive factors: 6/32 (19%) for none, 38/139 (27%) for 1, 129/260 (50%) for 2, 202/329 (61%) for 3, and 194/235 (83%) for 4 factors. Grade 2-4 treatment-related adverse events (AE) were experienced by 719 (67%) patients; 169 (16%) discontinued therapy for AE and 7 (0.6%) died during the PR tail.Naïve and experienced patients with advanced fibrosis or cirrhosis due to HCV-1 who have compensated bone marrow and liver function, can effectively and safely be treated by TVR triple therapy. Baseline predictors of outcome have been identified to optimize pre-treatment counselling.

Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management.This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia.Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (45 years), lower BMI (≤25 mg/m(2)) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment.These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring.

Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1)., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Background The Simeprevir ObservatioNal Effectiveness across practice seTtings (SONET) study evaluated the real-world effectiveness of simeprevir-based treatment for hepatitis C virus (HCV) infection. Methods The SONET study was a phase 4, prospective, observational, United States–based study enrolling patients ≥18 years of age with chronic genotype 1 HCV infection. The primary endpoint was the proportion of patients who achieved sustained virologic response 12 weeks after the end of treatment (SVR12), defined as HCV ribonucleic acid undetectable ≥12 weeks after the end of all HCV treatments. Results Of 315 patients (intent-to-treat [ITT] population), 275 (87.3%) completed the study. Overall, 291 were treated with simeprevir + sofosbuvir, 17 with simeprevir + sofosbuvir + ribavirin, and 7 with simeprevir + peginterferon + ribavirin. The majority of patients were male (63.2%) and white (60.6%); median age was 58 years, 71.7% had genotype/subtype 1a, and 39.4% had cirrhosis. The SVR12 was achieved by 81.2% (255 of 314) of ITT patients (analysis excluded 1 patient who completed the study but was missing SVR12 data); 2 had viral breakthrough and 18 had viral relapse. The SVR12 was achieved by 92.4% (255 of 276) of patients in the modified ITT (mITT) population, which excluded patients who discontinued treatment for nonvirologic reasons before the SVR12 time point or were missing SVR12 assessment data. Among mITT patients, higher SVR12 rates were associated with factors including age ≥65 years, non-Hispanic/Latino ethnicity, and employment status, but not genotype/subtype nor presence of cirrhosis. Simeprevir-based treatment was well tolerated; no serious adverse events were considered related to simeprevir. Conclusions In the real-world setting, simeprevir + sofosbuvir treatment was common and 92% of mITT patients achieved SVR12. Simeprevir-based treatment was effective and well tolerated in this cohort, including patients with cirrhosis.

The OSIRIS study investigated efficacy and safety of simeprevir plus sofosbuvir for eight or 12 weeks in hepatitis C virus (HCV) genotype 4-infected patients with METAVIR F0-F4 fibrosis. Sixty-three patients (33 treatment-naive and 30 peg-interferon/ribavirin (Peg-IFN/RBV)-experienced) enrolled in a partly randomized, open-label, multicentre, phase IIa study. Patients with F0-F3 fibrosis were randomized (1:1) into two groups (A1 and A2), stratified according to treatment experience and METAVIR score, to receive either eight weeks (Group A1, n=20) or 12 weeks (Group A2, n=20) of treatment. Patients with compensated cirrhosis (METAVIR F4) received 12 weeks of treatment (Group B, n=23). Treatment comprised simeprevir 150 mg and sofosbuvir 400 mg daily. The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Safety and tolerability were assessed throughout. Overall, 92% (95% CI: 82-97) of patients achieved SVR12; 75% (15/20) in Group A1 and 100% in groups A2 and B. Patients who did not achieve SVR12 (n=5) experienced viral relapse during the first 32 days following treatment and were all prior Peg-IFN/RBV null responders. The most commonly reported treatment-emergent adverse events (TEAEs) were asymptomatic lipase increase (14%), pruritus (14%), headache (13%) and hyperbilirubinaemia (11%). No patients discontinued due to TEAEs. In conclusion, simeprevir plus sofosbuvir for 12 weeks achieved a 100% SVR rate in HCV genotype 4-infected patients with or without compensated cirrhosis (ClinicalTrials.gov: NCT02278419). The AE and laboratory profile were favourable and consistent with previous data for simeprevir plus sofosbuvir in eight- and 12-week regimens.

Background: The disease profile of treatment-experienced HIV-1 patients (TEPs) looks different today compared with that of 5 years ago. Because less highly treated DUET patients may more closely resemble today’s TEPs, we conducted a post hoc efficacy and safety analysis of the pooled 96-week DUET data stratified by level of treatment experience. Methods: TEPs with HIV-1 were randomised to etravirine (ETR) 200mg twice daily (bid) or placebo bid with a background regimen for 48 weeks (plus optional 48-week extension). TEPs were categorized using 10 demographic and disease characteristics that in prior studies of treatment-experienced subjects had been associated with virologic response; patients meeting ≥5 criteria were categorized as less TEP. Results: 183 patients (men, 87.4%) who received ETR were less TEP and 413 patients (men, 91.0%) were more TEP. At baseline, more TEPs had more advanced disease, more previous antiretroviral (ARV) exposures and fewer options for active ARVs. At Week 96, for patients receiving ETR, response rates for the less TEP group and more TEP group were 68.3% and 52.8%, respectively. Incidence of adverse events (AEs) was similar between groups. A greater proportion of nonresponders in the more TEP group discontinued due to AEs (9.0% vs 5.5%) and virologic failure (18.9% vs 5.5%) compared with the less TEP group. Conclusion: Less TEPs had higher virologic response rates with ETR compared with more TEPs. Because the less TEP population from DUET more closely resembles TEPs with HIV-1 today, data from this subgroup may provide valuable information for real-life treatment decisions.

To examine how treatment adherence differences in ARTEMIS (96 week analysis) affected clinical outcome, and to assess factors impacting adherence.ARTEMIS is a Phase III trial, in HIV-1-infected treatment-naive patients, comparing efficacy and safety of once-daily darunavir/ritonavir (800/100 mg) versus lopinavir/ritonavir (800/200 mg total daily dose), each with a fixed-dose background tenofovir and emtricitabine regimen. Self-reported treatment adherence was assessed using the Modified Medication Adherence Self-Report Inventory (M-MASRI). In post-hoc analyses, mean adherence from weeks 4-96 was used to assess overall adherence for each patient, and transformed into a binary variable (95% , adherent;or = 95% , suboptimally adherent).Overall adherence was high: 83% of darunavir/ritonavir-treated patients and 78% of lopinavir/ritonavir-treated patients were95% adherent. The difference in virological response rate for adherent versus suboptimally adherent patients was smaller for darunavir/ritonavir (6% difference: 82% versus 76%, P = 0.3312) than for lopinavir/ritonavir (25% difference: 78% versus 53%, P0.0001). In suboptimally adherent patients, a higher virological response rate was seen with darunavir/ritonavir (76%) versus lopinavir/ritonavir (53%) (P0.01). Suboptimally adherent patients (both treatment groups) reported more adverse events (AEs), including gastrointestinal AEs, than adherent patients. Darunavir/ritonavir had a lower rate of AEs, including gastrointestinal AEs, than lopinavir/ritonavir, in adherent and suboptimally adherent patients.Suboptimal adherence had no significant effect on the virological response rate with once-daily darunavir/ritonavir treatment. In contrast, the lopinavir/ritonavir response rate was significantly reduced in suboptimally adherent patients compared with adherent patients. Once-daily darunavir/ritonavir resulted in a higher virological response rate in suboptimally adherent patients compared with lopinavir/ritonavir.

To evaluate the safety and antiviral activity of once-daily (qd) enfuvirtide (ENF) compared with twice daily (bid) ENF.T20-401 was a phase 2, open-label, randomized, 48-week pilot study comparing ENF 180 mg qd versus ENF 90 mg bid, added to an optimized background (OB) regimen. Patients were randomized 1:1 to receive ENF 180 mg qd given as two 90-mg injections (n = 30) or one 90-mg injection bid (n = 31), plus OB. The primary efficacy endpoint was the proportion of patients achieving a HIV-1 RNA viral load400 copies/mL. Adherence, pharmacokinetics, safety, and tolerability parameters, including injection site reactions (ISRs), were compared between treatment arms.At Week 48, 23.3% of patients on once daily versus 22.6% on twice daily (p = .969) reached400 copies/mL and 13.3% and 22.6% (p = .323), respectively, reached50 copies/mL. The proportion reporting 1 adverse event or ISRs was comparable between arms, despite an increased incidence of grade 4 erythema (13% vs. 0%), induration (33% vs. 12%), and ecchymosis (7% vs. 0%) on twice daily versus once daily. ENF adherence (95% of prescribed doses) was higher on once daily (80.0%) versus twice daily (58.1%).The antiviral efficacy, safety, and tolerability of 180 mg ENF qd appeared comparable with that of 90 mg ENF bid at Week 48, although the study was not powered to demonstrate the noninferiority of once daily versus twice daily.

High adherence rates to antiretroviral (ARV) therapy are associated with increased durability of viral suppression and decreased rates of drug resistance. The requirement of twice-daily subcutaneous self-administration of enfuvirtide (ENF) has raised concerns about adherence. This study assesses adherence to ENF and an optimized background (OB) of ARVs and its impact on virological and immunological responses during the TORO trials. Eighty-eight percent of patients in the OB arm reportedor = 85% adherence versus 87% of patients in the ENF + OB arm. Higher overall adherence was associated with improved virological and immunological response in both treatment arms at 48 weeks. In patients withor = 85% adherence, 33% of patients in the ENF + OB arm achieved HIV-1 RNA400 copies/ml, versus 13% in the OB arm (p0.0001). Similarly, patients withor = 85% adherence in the ENF + OB arm achieved a mean increase in CD4 cell count of 104 cells/mm(3) compared with 58 cells/mm(3) for patients in the OB arm (p0.001). None of the demographic factors explored (age, gender, race) or baseline characteristics (CD4 count, viral load, or baseline sensitivity score) was significant in predicting adherence to ENF when analyzed by multiple regression. Importantly, a history of intravenous drug use (IDU) was not associated with a significant decrease in adherence (mean adherence for IDU 96% versus mean adherence for non-IDU 96%; p = 0.825). Adherence was high in patients receiving the self-injectable ARV enfuvirtide. In addition, the inclusion of ENF did not negatively impact adherence to the ARV regimen as a whole.

Background and objective: In the face of increasing antiretroviral (ARV) treatment options and costs, payers are progressively challenged with prioritising resources. The cost effectiveness of the ARV agent enfuvirtide has been shown to be comparable to that of other available HIV treatment strategies, based on Markov modeling. However, an evaluation of enfuvirtide treatment costs that considers the impact of virological and immunological responses to therapy may provide a more clinically meaningful perspective for primary HIV healthcare providers. The aim of this study was to assess the cost per unit change in efficacy (HIV RNA decreases and CD4 count increases) of three different ARV regimens for triple class-experienced HIV-1 infected patients using actual drug costs and data from randomised, controlled clinical trials. Study design: The analysis included three steps. First, re-analysis of 48-week clinical trial data (T-20 vs Optimized Regimen Only [TORO]) to allow for a more direct comparison of enfuvirtide versus other commonly used ARV agents. All patients included in the re-analysis received a common optimised background (COB) regimen of three drugs: two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a ritonavir-boosted protease inhibitor (PI), lopinavir. HIV RNA levels and CD4 count changes were determined for three patient groups according to the treatment received —group 1: COB + enfuvirtide; group 2: COB + PI; group 3: COB + NRTI + PI. The second step of the analysis involved calculating the annualised regimen costs ($US wholesaler acquisition cost) for each patient group. In the third step, cost-efficacy ratios were calculated and compared between groups: (a) the annualised regimen cost ($US)/change in viral load from baseline, and (b) the annualised regimen cost ($US)/change in CD4+ cell count from baseline. Results: One hundred and fifty-seven patients were included in this previously unplanned secondary analysis (group 1: 79 patients; group 2: 42 patients; group 3: 36 patients). HIV RNA and CD4 count changes from baseline to week 48 were −1.80, −0.89 and −0.61 log 10 copies/mL (p < 0.001 for enfuvirtide vs each non-enfuvirtide group) and +102, +57 and +52 cells/mm3 (p < 0.05 for enfuvirtide versus each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The annualised costs of the combination therapies were $US35 624, $US27 549 and $US30 624; and the costs per 0.50 log 10 copies/mL HIV RNA decrease were $US9872, $US15 542 and $US24 907 (p < 0.05 for enfuvirtide vs each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The costs per 25 cells/ mm3 CD4 count increase were $US8722, $US12 127 and $US14 636 for subgroups 1, 2 and 3, respectively. Similar patterns in regimen cost per unit change were achieved after adjusting for baseline prognostic variables. The incremental cost-efficacy ratios for group 1 versus the combination of groups 2 and 3 were $US3124 for HIV RNA reduction and $US3239 for CD4 count increase. Conclusion: Enfuvirtide-containing regimens are associated with higher cost as well as improved virological and immunological outcomes when compared with alternative four- and five-drug regimens. When costs and outcomes are considered jointly, an enfuvirtide-based regimen is more cost efficacious than alternative regimens in this patient population.

Determinants of therapeutic success are poorly characterized in patients with extensive HAART experience. Positive prognostic factors (PPFs) in the TORO trials could serve as the basis for a prognostically meaningful staging of treatment-experienced patients initiating a new antiretroviral regimen.In TORO, triple-class-experienced patients with viral load (VL)or = 5,000 copies/mL received an optimized background regimen of 3-5 antiretrovirals (based on treatment history and baseline resistance testing) +/- enfuvirtide (n = 995). Clinically relevant baseline PPFs that were predictive of 48-week virologic outcomes were identified via multiple regression analyses.The likelihood of VL400 copies/mL at 48 weeks (ITT analysis) was greater for those patients who had baseline CD4 countor = 100 cells/mm3 (odds ratio [OR] 2.1; 95% confidence intervals [CIs] 1.5, 3.1); baseline VL5 log10 copies/mL (OR 1.8; 95% CIs 1.2, 2.6); receivedor = 10 prior antiretrovirals (OR 2.4; 95% CIs 1.6, 3.4); or receivedor = 2 active antiretrovirals in their background treatment regimen (OR 2.3; 95% CIs 1.6, 3.3). Overall, 67% of triple-class-experienced patients who met all four prognostic criteria and received enfuvirtide achieved VL400 copies/mL at 48 weeks vs. 43% for non-enfuvirtide patients (p.05). Similar results were obtained when the analysis was done separately in each of the randomization arms of the study.Our findings provide guidance for physicians on expected outcomes in treatment-experienced patients and should be of value in their clinical management, as well as in stratifying participants in clinical trials involving treatment-experienced patients.

The three main components of long-term efficacy for a combination of antiretrovirals are: (i) the strength of the antiviral effect, (ii) toxicity profile and (iii) patient acceptability of the regimen. Intent-to-treat (ITT) analysis, where discontinuations and switches are considered failures [ITT, switch equals failure (ITT/S=F)], is a regulatory standard for analysing the efficacy of anti-retrovirals. A review of all clinical trials published in FDA product labels was conducted, including all clinical trials of boosted protease inhibitor- or nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in treatment-naive patients, and all clinical trials of antiretrovirals in treatment-experienced patients. Clinical trials where the results are presented in the standard ITT/S=F method were included. For randomized clinical trials in treatment-naive patients, the majority of treatment discontinuations have been either for toxicity (32%) or patient refusal of treatment (41%), with only 27% of failure endpoints for virological reasons among recent clinical trials in naive patients. Therefore, there is the potential for the results from ITT/S=F analysis to be driven by non-virological endpoints – a new treatment can be classified as ‘more efficacious’ than control owing to fewer discontinuations due to adverse events or patient preference. In order to understand the intrinsic potency of the anti-retroviral regimen under study, ITT analysis needs to be supplemented by standardized as-treated analyses, excluding withdrawals for toxicity or other reasons. To evaluate the efficacy of a treatment strategy or sequential treatment regimens, the ‘ITT, switch included’ (ITT/SI) method: where changes from the initial randomized treatment are not classified as treatment failure – can be used. However, interpretation of clinical trials using ITT/SI analysis is difficult and depends on the frequency of treatment switching in the different arms of a trial. Conclusions on efficacy from clinical trials can depend on the primary analysis used; most commonly, treatments could be significantly different by ITT/S=F analysis, but then interpreted as equivalent using the ITT/SI or as-treated methods.

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve.Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve.Results. Overall, 272 patients received DRV/r ODn=135or BIDn=137plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was4.10 log10⁡copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression

Background: Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002. Methods: 1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4. Results: Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intentionto- treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events. Conclusions: FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments., SCOPUS: ar.j, info:eu-repo/semantics/published

Methods of sampling patients for resistance testing, and statistical analyses of HIV drug resistance, have not been standardised in HIV clinical trials. We analysed methods of genotyping and rates of treatment-emergent drug resistance from 27 clinical trials identified from a MEDLINE search. Sample size calculations were conducted using NQUERY software, assuming 5% significance level, 80% power and 1:1 randomisation. The percentage of patients with treatment-emergent IAS–USA mutations after 96 weeks ranged from 1.8% to 9.1% for first-line 2NRTI/NNRTI treatments, 0.6% to 6.3% for first-line 2NRTI/PI/r treatments and 0.0% to 2.0% in switch trials of boosted PIs. The prevalence of drug resistance was higher in trials with no screening for drug resistance at baseline, where the HIV RNA cut-off for genotyping was >50 copies/mL, where patients were tested for drug resistance after discontinuation of treatment, and where follow-up times were 96 weeks or longer. HIV clinical trials could be designed to detect differences in the risk of HIV drug resistance between treatments, as an analysis supporting HIV RNA suppression as the primary endpoint. However, this would require a standardised approach, with intent-to-treat analyses, testing of all samples with HIV RNA>50 copies/mL and genotyping after drug discontinuation.

AIM To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

The Patient Medication Adherence Questionnaire Version 1.0 (PMAQ-V1.0) is a patient-reported adherence instrument to assess medication-taking behaviors and identify barriers to adherence with antiretroviral therapy. To assess the correlation between adherence and virologic outcome, the PMAQ-V1.0 was administered to 194 antiretroviral-experienced adults with HIV infection enrolled in a 16-week evaluation of protease inhibitor-containing regimens featuring a lamivudine/zidovudine combination tablet. At baseline, plasma HIV-1 RNA levels were less than 10,000 copies/mL and CD4(+)-cell counts were equal to or greater than 300 x 10(6)/L; patients had been receiving a conventional regimen of lamivudine + zidovudine (separately) plus a protease inhibitor for at least 10 weeks immediately prior to the study. Forty-eight percent of patients who reported missing at least one dose of a nucleoside reverse-transcriptase inhibitor (NRTI) during the study had detectable plasma HIV-1 RNA, compared with 26% of patients who reported no missed doses (P = .002). Patients who missed at least one dose of an NRTI or protease inhibitor were 2.5 times more likely to have quantifiable HIV-1 RNA than those who reported no missed doses. Patients who reported fewer barriers and more motivators to adherence had better virologic outcomes (P = .001). Several dimensions of the PMAQ-V1.0 did not function as well as hypothesized. In this study, self-reported adherence derived from the PMAQ-V1.0 predicted virologic outcomes, but further refinement of the dimensions appears warranted.

Context: There is little information available on the correlation between HIV-1 RNA level, CD4 cell count and the risk of progression to AIDS or death during treatment with reverse transcriptase inhibitors. Objectives: To define the correlation between HIV-1 RNA level, CD4 cell count and the 1 year risk of progression to AIDS or death. Design: Pooled analysis of six randomized clinical trials of zidovudine/lamivudine versus control treatments. Setting: Investigational sites in Europe, North America, Australia and South Africa. Patients: The trials recruited 1488 adult HIV-1-infected male and female patients aged ≥ 18 years, with inclusion CD4 cell count between 25 and 500 x 10 6 cells/l. Patients were either nucleoside analogue-naive or pre-treated, and at all stages of HIV-1 disease. Main outcome measures: Progression (defined as all new and recurrent AIDS-defining events or death) was correlated with the HIV-1 RNA level and CD4 cell count during the first 8 to 52 weeks of treatment. Results: During a median 1 year follow up, progression was largely restricted to patients with both low CD4 cell count (≤ 200 x 10 6 cells/l) and high HIV-1 RNA level (> 5000 copies/ml). There was an increase in the incidence of progression events with rises in HIV-1 RNA level > 5000 copies/ml and reductions in CD4 cell count under 200 x 10 6 cells/l. The events occurring with HIV-1 RNA ≤ 5000 copies/ml were generally atypical. Conclusions: Progression to AIDS or death is rare for patients with HIV-1 RNA ≤ 5000 copies/ml, particularly when CD4 cell count is more than 200 x 10 6 cells/l.

Item does not contain fulltext OBJECTIVE: Insulin resistance is a predictor of poor response to peginterferon/ribavirin in patients infected with the chronic hepatitis C virus (HCV). There are no data on direct-acting antivirals. This exploratory analysis assessed the effect of metabolic factors and insulin resistance, measured by homoeostatic model assessment (HOMA), on virological response to telaprevir in Study C208. DESIGN: Overall, 161 HCV genotype 1-infected, treatment-naive patients received 12 weeks of telaprevir plus peginterferon/ribavirin, then 12/36 weeks of peginterferon/ribavirin depending on on-treatment response criteria. The prognostic significance of several factors, including HOMA-insulin resistance (HOMA-IR), on virological response at weeks 4 and 12, end of treatment and 24 weeks after treatment was explored by multiple regression analysis. RESULTS: Baseline HOMA-IR data were available for 147 patients; baseline characteristics were consistent with the overall population. Baseline HOMA-IR 4 was seen in 54%, 30% and 16% of patients, respectively. Neither response rates (any time point) nor week 4 viral load decline were significantly influenced by baseline HOMA-IR. In multivariate analyses, fibrosis stage and low-density lipoprotein cholesterol level were predictive of sustained virological response (OR 0.47 and 1.02, respectively). After the end of treatment, HOMA-IR was significantly lower in patients with sustained virological response than in those without (0.61 vs 1.34 for relapsers and 1.15 for non-responders; p

ARTEMIS demonstrated significantly greater efficacy of once-daily darunavir/ritonavir (DRV/r) 800/100 mg versus lopinavir/ritonavir 800/200 mg (total daily dose) in treatment-naïve, HIV-1-infected patients at week 96. The influence of baseline characteristics on efficacy and safety was analyzed in DRV/r patients.Patients received once-daily DRV/r plus fixed-dose tenofovir/emtricitabine. Week 96 efficacy and safety data were analyzed by gender (males, n=239; females, n=104), age (≤30, n=115; 31-45, n=175;45, n=53), race (Asian, n=44; Black, n=80; Caucasian/White, n=137; Hispanic, n=77), and hepatitis B and/or C virus coinfection (n=43).Week 96 virologic response rates (HIV-1 RNA50 copies/mL) were as follows: gender: 79% for both males and females; age: 72% (≤30), 81% (31-45), and 89% (45); race: 96% (Asian), 71% (Black), 77% (Caucasian/White), and 79% (Hispanic); coinfection status: 72% (coinfected) and 80% (non-coinfected). The incidence of treatment-related adverse drug reactions (ADRs) and laboratory abnormalities were comparable across gender, age, and race subgroups. Coinfected patients had a higher incidence of liver-related ADRs than non-coinfected patients.DRV/r 800/100 mg qd is an effective, well-tolerated treatment option for treatment-naïve patients of different gender, age, race, or coinfection status.

of response (28.9%), personal reasons (29.6%), adverse events (AEs, 38.2%), decompensation (1.3%). 263/500 (52.6%) obtained a sustained virological response (SVR), 71 (14.2%) relapsed and 61 (12.2%) were non-responders. Treatment outcome information were not available in 105/500 (21%) since: lost on-treatment (33.3%), lost during follow-up (25.7%), withdrawn for AEs (19.1%), administrative reasons (21.9%). Based on HCV genotype, intention-to-treat (n = 500) and per-protocol (n = 395) analyses of SVR rates are shown in Table 1.

T-1249 is a peptide HIV fusion inhibitor (FI) previously under development for use in FI-naive and experienced patients. Here we present prospectively planned longitudinal analyses of FI resistance during 48 weeks of T-1249 dosing in patients with extensive prior FI exposure. T1249-105 was a single-arm rollover study in patients with prior resistance to enfuvirtide (ENF) and 10 days of T-1249 functional monotherapy exposure. The phenotype and genotype of plasma virus envelopes were analyzed at baseline and at study weeks 8, 16, and 48. At study entry, viruses had a geometric mean decrease in susceptibility to ENF of 51.8-fold but to T-1249 of 1.8-fold; extensive genotypic resistance to ENF was observed. A median viral load response of - 1.5 log(10) copies/ml was observed at week 2 that was partially sustained (- 0.5 log(10) copies/ml) through 48 weeks. Resistance to T-1249 gradually increased to a geometric mean 92.7-fold decrease from FI-naive baseline; this occurred concomitant with further evolution of gp41 amino acids 36-45, most commonly the G36D (n = 6, 16%) or N43K (n = 9, 24%) substitutions. A novel substitution, A50V (n = 12, 32%), was also common, as were the N126K and S138A substitutions in heptad-repeat 2 (HR-2). These data point toward a primary role for the gp41 36-45 locus in modulating FI binding and suggest that residues in HR-2 may contribute in a more limited manner to development of peptide FI resistance. These data also point toward a substantial genetic barrier and fitness cost to development of resistance to next-generation fusion inhibitors.

The additional 48-week optional treatment extension of the T-20 versus Optimized Regimen Only (TORO) studies evaluated long-term safety and efficacy of enfuvirtide (ENF) through week 96 in patients receiving ENF plus optimized background (OB) and patients switching to ENF plus OB from OB alone. Patient randomization was 2:1 to ENF plus OB (n = 663) and OB (n = 334), of which 89.7% and 89.8% were male, 89.3% and 88.6% were Caucasian, and median age was 41 and 42 years, respectively. HIV risk factors were comparable between the ENF plus OB and OB groups with the major factors being 65.2% versus 66.2% homosexual contact, 17.8% versus 19.8% heterosexual contact, 4.1% versus 4.8% bisexual contact, respectively, and 6.9% injection drug use in both groups. OB patients were allowed to switch to ENF plus OB at virologic failure before week 48 and required to switch at week 48 to continue in the study (n = 230). Efficacy and safety assessments were conducted for each group. At week 96, 55% of ENF plus OB subjects completed the study and 26.5% achieved a viral load of less than 400 copies per milliliter (17.5% achieved less than 50 copies per milliliter). Viral load and CD4 mean change from baseline was -2.1 and -1.1 log(10) HIV-1-RNA copies per milliliter and +166 and +116 CD4 cells/mm(3) for ENF plus OB and switch patients, respectively. No new ENF-related safety issues emerged in weeks 48-96. Injection site reactions led to discontinuation in 7% and 10% of ENF plus OB and switch patients, respectively. In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial.

OBJECTIVE To compare the effectiveness of three drug combination antiretroviral therapy (ART) in treatment-naive HIV-infected persons, and identify the predictors of responses. DESIGN AND METHODS Overview of trials identified by searching public domain publications and conference presentations. The three-drug combination therapy was defined as two nucleoside reverse transcriptase inhibitors (NRTI) or nucleotide and NRTI, and either: (1) a protease inhibitor (PI); (2) a non-nucleoside RTI (NNRTI); (3) a third NRTI; or (4) a ritonavir-boosted PI (BPI). Week 24 and 48 results for the proportions of patients with plasma HIV RNA levels < 400 and < 50 copies/ml, and change in CD4(+) cell counts were recorded. RESULTS Fifty-three trials met the entry criteria, and enrolled 14 264 patients into 90 treatment arms. Overall 55% of patients had plasma HIV RNA levels < 50 copies/ml at week 48 and this percentage increased with later publication dates. In unadjusted pairwise comparisons at week 48, significantly greater percentages of patients receiving NNRTI (64%) and BPI (64%) had RNA < 50 copies/ml than NRTI (54%) or PI (43%), and CD4(+) cell count increases were significantly greater in the BPI group (+200 cells/microl) than the PI (+179), NNRTI (+173), or NRTI (+161) groups. Pill count and percentage of patients with week 48 plasma HIV RNA levels < 50 copies/ml were correlated in the univariate analysis (P = 0.0053; r = -0.323), but pill count was not a significant predictor in the multivariate analyses. Drug class and baseline CD4(+) cell counts were significant predictors, but explained only a modest amount of the treatment effect, (R(2) = 0.355). CONCLUSIONS NNRTI and BPI-containing regimens offer superior virologic suppression over 48 weeks, supporting existing guidelines for the choice of initial ART. Pill count was not a consistent predictor of virologic suppression.

Background: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. Methods: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. Results: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. Conclusion: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in

BACKGROUND The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. METHODS The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. RESULTS A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline

BACKGROUND T-1249 is a 39-amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF). METHODS A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1-infected adults with detectable viremia while on an ENF-containing treatment regimen. RESULTS From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold, and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients. CONCLUSIONS These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced.

The T-20 vs. Optimized Regimen Only Study 2 (TORO 2) compared the efficacy and safety of 24 weeks of treatment with the fusion inhibitor enfuvirtide in combination with an optimized background antiretroviral regimen with the efficacy and safety of the optimized background regimen alone. The patients had previous treatment with each of the three classes of antiretroviral drugs, documented resistance to each class, or both and a plasma level of human immunodeficiency virus type 1 (HIV-1) RNA of at least 5000 copies per milliliter. They were randomly assigned in a 2:1 ratio to receive either enfuvirtide (90 mg twice daily) plus a background regimen optimized with the aid of resistance testing (enfuvirtide group) or the background regimen alone (control group). Of the 512 patients who underwent randomization, 335 in the enfuvirtide group and 169 in the control group received at least one dose of study medication and had at least one follow-up measurement of plasma HIV-1 RNA. The median base-line plasma HIV-1 RNA level was 5.1 log10 copies per milliliter in both groups. The median CD4+ cell count was 98.0 cells per cubic millimeter in the enfuvirtide group and 101.5 cells per cubic millimeter in the control group. Patients had a median of seven years of previous treatment and had received a median of 12 antiretroviral drugs. The background regimen comprised a mean of four antiretroviral drugs in both groups. At 24 weeks, the least-squares mean change from base line in the plasma viral load (intention-to-treat, last observation carried forward) was a decrease of 1.429 log10 copies per milliliter in the enfuvirtide group and a decrease of 0.648 log10 copies per milliliter in the control group, a difference of 0.781 log10 copies per milliliter (P

Plasma human immunodeficiency virus (HIV) RNA levels correlate closely with clinical prognosis in both treated and untreated HIV-infected persons and are widely used to guide clinical practice and as a primary end point in clinical trials. Thus, variability in these measurements may significantly affect their interpretation in clinical practice and research. The variability in consecutive measurements of plasma HIV RNA levels was studied in 387 subjects receiving either stable nucleoside reverse transcriptase inhibitor therapy or no treatment. The Pearson's correlation coefficient between baseline measures 2 weeks apart was 0.92. The mean SD in consecutive measurements 1 month apart was 0.31 log 10 copies/mL with a 95% tolerance limit of 0.7 log 10 copieslmL (5-fold). Two-thirds of the total variance in consecutive measures 1 month apart was due to biologic fluctuation; one-third was due to assay variance. The biologic variance increased proportionately with the number of weeks between assessments. Clinicians and investigators should be aware of the magnitude of variability in viral RNA levels in the HIV-infected population.

Objective To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment. Design and setting The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1 year. Patients This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for clinical progression. Main outcome measures The correlation between 12-20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA. Results After 12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10 at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x 10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71). Conclusions Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial.

Previous uncontrolled reports have suggested that H2-antagonists may possess immunomodulatory activity in human immunodeficiency virus (HIV)-infected patients. Such trials reported improvements in HIV-related symptoms, increased absolute CD4 cell numbers, and improvements in other measures of host immunity. The present trial was a randomized, placebo-controlled, double-blind trial of ranitidine 300 mg (orally twice daily) in subjects with early HIV infection (absolute CD4 cells, 400-700/mm3). Eighty-one subjects entered the trial and 73 completed 16 weeks on study medications. There were no significant differences in the time-weighted average change from baseline between the 2 treatment groups in absolute CD4 cell number, plasma HIV RNA level, or most other surrogate markers of HIV infection. Serum beta2-microglobulin levels were significantly lower in placebo than ranitidine recipients. Ranitidine should not be recommended for the treatment of HIV-infected patients unless it is used for established indications.