Showing papers by "Chloe Orkin published in 2014"

Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy

Abstract: Objective: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). Methods: Patients aged more than 20 years who started ART during 2000-2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012.Wedetermined the latestCD4+ cell count and viral load before ART and in each of years 1-5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4+ cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20-85 years. Results: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 personyears. At start of ART, expected age at death [95% confidence interval (CI)] of 35-yearold men with CD4+ cell count less than 200, 200-349, at least 350 cells/ml was 71 (68- 73), 78 (74-82) and 77 (72-81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4+ cell count in the first year of ART from less than 200 to 200-349 or at least 350 cells/ml and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48-61) (CD4+ cell count <200 cells/ml and no viral suppression) to 80 (76-83) years (CD4+ cell count 350 cells/ml and viral suppression). Conclusion: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4+ cell count significantly improve their life expectancy if they have a good CD4+ cell count response and undetectable viral load.

Simeprevir (TMC435) With Pegylated Interferon/Ribavirin in Patients Coinfected With HCV Genotype 1 and HIV-1: A Phase 3 Study

Abstract: Background. Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection. Methods. Patients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received responseguided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Results. One hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-fourof 61 eligible patients (88.5%) met RGT criteriafor 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0–F2 and F3–F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal. Conclusions. Simeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection. Clinical Trials Registration. NCT01479868.

HIV status does not impair the outcome of patients diagnosed with diffuse large B-cell lymphoma treated with R-CHOP in the cART era.

Abstract: Objective To compare the outcome of patients diagnosed with HIV infection and diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP in the cART era with that of a HIV-negative control group. Methods From 2003 to 2011, 305 patients (97 HIV-positive) were diagnosed with DLBCL and treated with R-CHOP. Clinical features were compared using chi-square or Fisher's exact test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed using the Cox regression proportional hazards model. Results HIV-positive patients had more B symptoms and extranodal sites of disease at diagnosis, but the proportion of patients with high-intermediate/high-risk disease according to the international prognostic index (IPI) was similar between groups. Response rate was 73%, both for patients with and without HIV infection. After a median follow-up of 48 months, 30 patients relapsed after achieving a complete remission, including four HIV-positive patients. Ninety-six patients have died (19 HIV-positive), 73 of them due to DLBCL. Three patients (one HIV-positive) died due to treatment toxicity. Patients with HIV infection had a significantly longer disease-free survival (DFS) (5-year: 94 vs. 77%; P = 0.03) and overall survival (OS) (78 and 64% for HIV-positive and HIV-negative patients, respectively; P = 0.03). These results were confirmed on multivariate analysis when controlled for other potential prognostic confounders. Conclusion HIV-positive patients diagnosed with DLBCL in the cART era have an excellent outcome when treated with standard immunochemotherapy. Therefore, the choice of chemotherapy in patients with lymphoma should not be influenced by HIV status.

Change in vitamin D levels and risk of severe vitamin D deficiency over 48 weeks among HIV-1-infected, treatment-naive adults receiving rilpivirine or efavirenz in a Phase III trial (ECHO).

Abstract: BackgroundThis analysis assessed changes in serum 25-hydroxyvitamin D (25[OH]D; the precursor form of active vitamin D) in antiretroviral-naive adults receiving rilpivirine or efavirenz over 48 wee...

Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤ 100 000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials.

Abstract: Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis.

Abstract: The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naive patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naive subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96.

Sensitive testing of plasma HIV-1 RNA and Sanger sequencing of cellular HIV-1 DNA for the detection of drug resistance prior to starting first-line antiretroviral therapy with etravirine or efavirenz

Abstract: Methods: We carried out retrospective testing of baseline samples from patients entering the SENSE trial of firstline ART in Europe, Russia and Israel. Prior to randomization to etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma samples underwent routine Sanger sequencing of HIV-1 RT and protease (plasmaSS) in order to exclude patients with transmitted RAMs. Retrospectively, Sanger sequencing was repeated with HIV-1 DNA from baseline peripheral blood mononuclear cells (PBMCSS); baseline plasma samples were retested by allele-specific PCR targeting seven RT RAMs (AS-PCR) and ultra-deep RT sequencing (UDS). Results: By plasmaSS, 16/193 (8.3%) patients showed ≥1 transmitted RAM affecting the NRTIs (10/193, 5.2%), nonnucleoside reverse transcriptase inhibitors (4/193, 2.1%) or protease inhibitors (2/193, 1.0%). No additional RAMs were detected by AS-PCR (n¼ 152) and UDS (n¼ 24); PBMCSS (n¼ 91) yielded two additional samples with one RAM each. Over 48 weeks, 4/79 (5.1%) patients on etravirine and 7/78 (9.0%) on efavirenz experienced virological failure; none had baseline RAMs. Conversely, 11/79 (13.9%) patients randomized to etravirine had one polymorphic RAM from the etravirine score in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes. Conclusions: The detection of resistance increased marginally with PBMC testing but did not increase with sensitive plasma testing. A careful consideration is required of the cost-effectiveness of different strategies for baseline HIV drug resistance testing.

Vitamin D deficiency in HIV: a shadow on long-term management?

Abstract: Vitamin D deficiency in HIV infection has attracted much interest. The best known clinical outcomes of vitamin D deficiency are rickets (children) and osteomalacia (adults). Several non-skeletal disorders have also been linked to suboptimal vitamin D levels in the general population. The prevalence of vitamin D deficiency varies widely (6-100%) across diverse patient populations, with no evidence that it is higher in HIV-positive versus noninfected adults. Vitamin D deficiency may blunt immune restoration and exacerbate HIV complications (e.g. opportunistic infections, poor perinatal outcomes, wasting, HIV disease progression, AIDS events, and death). The nonnucleoside reverse transcriptase inhibitor efavirenz was associated with a relatively high risk of vitamin D deficiency; nevirapine, etravirine, and rilpivirine were noted to have less or no impact on vitamin D versus efavirenz in the limited data available. Protease inhibitors have either no or a low association with vitamin D deficiency. Nucleoside/nucleotide reverse transcriptase inhibitors (with the possible exception of zidovudine) also did not appear to be associated with vitamin D deficiency. Management of vitamin D deficiency in HIV-positive adults has not been rigorously evaluated; some guidelines recommend more vitamin D supplementation for HIV-positive adults on antiretrovirals versus the general population (e.g. 2-3 times higher vitamin D daily intake for the age group; loading dose up to 10,000 IU/day for 8-10 weeks and a maintenance dose of 800-2,000 IU/day). In conclusion, although vitamin D deficiency in HIV-positive adults can be prevalent, current evidence for its causes and impact is relatively weak. More data, particularly from large, controlled, long-term trials, regarding the benefits of correcting vitamin D levels in HIV-positive adults are needed.

Failure to achieve a CD4+ cell count response on combination antiretroviral therapy despite consistent viral load suppression.

Abstract: Objective: To assess CD4+ cell count recovery in people severely immunosuppressed at start of antiretroviral therapy (ART) who achieve and maintain viral load suppression. Methods: Eligible participants from the UK Collaborative HIV Cohort Study started ART with at least three drugs after 1 January 2000. Participants were required to have pre-ART CD4+ cell count below 100 cells/μl, at least 2 years of follow-up on ART, have achieved viral load suppression (≤50 copies/ml) by 9 months after starting ART and to have maintained this throughout follow-up. Participants were further required to be regularly engaged with care. We calculated the proportion of people who failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500 cells/μl by the time of the last follow-up, or 5 years from start of ART, whichever occurred first (censoring date). Results: Of the 400 participants [median (interquartile range) pre-ART CD4+ cell count of 38 (14–65) cells/μl], 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500 cells/μl, by the censoring date, respectively. Kaplan–Meier estimates of the proportion of people reaching each CD4+ cell count threshold after 1 year on ART were 88, 70, 50, 14 and 3%, respectively, and after 3 years on ART, 98, 95, 90, 59 and 25%, respectively. Median (interquartile range) follow-up on ART was 3.9 (2.7–4.8) years. Conclusion: Given a person with pre-ART CD4+ cell count below 100 cells/μl survives and maintains consistent viral load suppression on ART, there is over a 90% chance of reaching a CD4+ cell count above 200 cells/μl by 3 years.

Simeprevir for the treatment of hepatitis C and HIV/hepatitis C co-infection.

Abstract: Hepatitis C virus (HCV) is a major cause of chronic hepatitis in 170 million people worldwide and can progress to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, a disease process accelerated in HIV co-infection. Approximately 25% of HIV infected people are co-infected with HCV (worldwide prevalence 4–5 million) and up to 16.7% of deaths in this population are attributable to HCV co-infection. Previous treatment options for HCV were limited to pegylated interferon and ribavirin (PEG-IFN/RBV), a combination that demonstrated lower successful cure rates in genotype 1 HCV mono-infection and HIV/HCV co-infection, and is also associated with a considerable adverse side-effect profile. The development of directly acting antivirals (DAAs) offers the first class of drug to achieve good viral suppression in previously hard-to-treat patient groups. We review the benefits, tolerability and drug interactions with concomitant drugs of the DAA simeprevir for patients who have HCV mono-infection and hep...