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1.  How can we achieve universal access to low-cost treatment for HIV? 
Journal of Virus Eradication  null;2(4):193-197.
Abstract
Mass production of low-cost antiretrovirals (ARVs) has already allowed over 17 million individuals to access treatment for HIV infection, mainly in low-income countries. It is possible to manufacture combination ARVs for $110 per person-year, using tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). New combinations of ARVs costing as little as $60 per person-year will be available in the near future. Pre-exposure prophylaxis using TDF in combination with either 3TC or emtricitabine (FTC) could also be provided for less than $90 per person-year.
Voluntary licensing allows people in the poorest countries to access new ARVs at prices close to manufacturing costs. Patents on several key ARVs will expire by 2018 and should allow worldwide access to high-quality, low-cost triple combination therapy, such as TDF/3TC/EFV. Several protease inhibitors will also become available as generics by 2018. However, ongoing patent restrictions will lead to sustained high prices for the most recently developed ARVs in most middle- and high-income countries. These include the nucleotide tenofovir alafenamide, the integrase strand inhibitor dolutegravir and several single combination tablet regimens.
We suggest that as patents for ARVs expire, health authorities first need to rapidly import and introduce generic versions of drugs such as abacavir, 3TC, EFV and TDF. Once these low prices have been established for these generics, cost-effectiveness of patented ARVs needs to be re-evaluated. It may no longer be justified to pay high prices for these drugs. A strategy of low-cost generic ARVs for most people, with higher-cost patented alternatives used as switch options, could allow for an increased number of people to receive ARVs in the context of fixed health budgets.
PMCID: PMC5075345  PMID: 27781100
antiretrovirals; nucleoside analogues; protease inhibitors; non-nucleosides; integrase strand inhibitors; health economics
2.  HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK 
Journal of Antimicrobial Chemotherapy  2016;71(12):3487-3494.
Background
Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings.
Objectives
We examined darunavir DRMs emerging in clinical practice in the UK.
Patients and methods
Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls.
Results
Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group.
Conclusions
Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility.
doi:10.1093/jac/dkw343
PMCID: PMC5181398  PMID: 27856703
3.  Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation 
Jose, S | Quinn, K | Dunn, D | Cox, A | Sabin, C | Fidler, S | Ainsworth, Jonathan | Allan, Sris | Anderson, Jane | Babiker, Abdel | Chadwick, David | Delpech, Valerie | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hay, Phillip | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Martin, Fabiola | Nelson, Mark | Orkin, Chloe | Palfreeman, Adrian | Phillips, Andrew | Pillay, Deenan | Post, Frank | Pritchard, Jillian | Sachikonye, Memory | Schwenk, Achim | Tariq, Anjum | Walsh, John | Thornton, Alicia | Glabay, Adam | Perry, N | Tilbury, S | Youssef, E | Churchill, D | Everett, R | Asboe, D | Mandalia, S | Korat, H | Taylor, C | Gleisner, Z | Ibrahim, F | Campbell, L | Brima, N | Williams, I | Youle, M | Lampe, F | Smith, C | Tsintas, R | Chaloner, C | Hutchinson, S | Huntington, S | Mackie, N | Winston, A | Weber, J | Ramzan, F | Carder, M | Lynch, J | Hand, J | Souza, C | Munshi, S | Miller, S | Wood, C | Wilson, A | Morris, S | Allan, S | Palfreeman, A | Memon, K | ewszuk, A | Chadwick, D | Cope, E | Gibson, J | Kegg, S | Main, P | Mitchell, Dr | Hunter, Dr | Hay, P | Dhillon, M | Martin, F | Russell‐Sharpe, S | Harte, A | Clay, S | Tariq, A | Spencer, H | Jones, R | Atkinson, C | Delpech, V | Sachikonye, M | Aitken, Celia | Pozniak, Anton | Cane, Patricia | Clark, Duncan | Collins, Simon | Douthwaite, Samuel | White, Ellen | Fraser, Christophe | Geretti, Anna Maria | Hale, Antony | Hué, Stéphane | Kaye, Steve | Kellam, Paul | Lazarus, Linda | Leigh‐Brown, Andrew | Mbisa, Tamyo | Moses, Samuel | Nastouli, Eleni | Smit, Erasmus | Templeton, Kate | Tilston, Peter | Webster, Daniel | Zhang, Hongyi | Greatorex, Jane | Mullen, Jane | Tandy, Richard | Fawcett, Tracy | Hopkins, Mark | Ashton, Lynn | Booth, Claire | Garcia‐Diaz, Ana | Shepherd, Jill | Schmid, Matthias L | Payne, Brendan | Pere, Spiro | Hubb, Jonathan | Kirk, Stuart | Gunson, Rory | Bradley‐Stewart, Amanda
HIV Medicine  2015;17(5):368-372.
Objectives
No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development.
Methods
In a large cohort of HIV‐positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART.
Results
Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL.
Conclusions
We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL.
doi:10.1111/hiv.12302
PMCID: PMC4949527  PMID: 26306942
antiretroviral therapy; CD4 count; HIV resistance; virological failure
4.  Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study 
Supplemental Digital Content is Available in the Text.
Abstract:
This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine.
doi:10.1097/QAI.0000000000000904
PMCID: PMC4804741  PMID: 26605505
atazanavir; efficacy; HIV-1; raltegravir; switch study; tolerability; resistance
5.  Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study 
Supplemental Digital Content is Available in the Text.
Background:
Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment.
Methods:
We enrolled virologically suppressed HIV-1-infected subjects with estimated creatinine clearance (CrCl) 30–69 mL/min in a single-arm, open-label study to switch regimens to E/C/F/TAF. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formulae. This study is registered with ClinicalTrials.gov, number NCT01818596.
Findings:
We enrolled and treated 242 patients with mean age 58 years, 18% Black, 39% hypertension, 14% diabetes. Through week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had significant improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001 for all). Hip and spine bone mineral density significantly increased from baseline to week 48 (mean percent change +1.47 and +2.29, respectively, P < 0.05). Ninety-two percent (222 patients) maintained HIV-1 RNA <50 copies per milliliter at week 48.
Interpretation:
Switch to E/C/F/TAF was associated with minimal change in GFR. Proteinuria, albuminuria and bone mineral density significantly improved. These data support the efficacy and safety of once daily E/C/F/TAF in HIV+ patients with mild or moderate renal impairment without dose adjustment.
doi:10.1097/QAI.0000000000000908
PMCID: PMC4804743  PMID: 26627107
tenofovir alafenamide; emtricitabine; chronic kidney disease; bone mineral density; HIV
6.  Choice of antiretroviral drugs for continued treatment scale-up in a public health approach: what more do we need to know? 
Introduction
There have been several important developments in antiretroviral treatment in the past two years. Randomized clinical trials have been conducted to evaluate a lower dose of efavirenz (400 mg once daily). Integrase inhibitors such as dolutegravir have been approved for first-line treatment. A new formulation of tenofovir (alafenamide) has been developed and has shown equivalent efficacy to tenofovir in randomized trials. Two-drug combination treatments have been evaluated in treatment-naïve and -experienced patients. The novel pharmacokinetic booster cobicistat has been compared to ritonavir in terms of pharmacokinetics, efficacy and safety. The objective of this commentary is to assess recent developments in antiretroviral drug treatment to determine whether new treatments should be included in new international guidelines.
Discussion
The use of first-line treatment with tenofovir and efavirenz at the standard 600 mg once-daily dose should remain the first-choice standard of care treatment. Evidence supporting a switch to efavirenz 400 mg once daily or integrase inhibitors is sufficient to consider these drugs as alternative first-line options, but more data are needed on their use in pregnant women and people with TB co-infection. The use of new formulations of tenofovir is currently too preliminary to justify immediate adoption and scale-up across HIV programmes in low- and middle-income countries. The evidence supporting use of two-drug combinations is not considered strong enough to justify changed recommendations from use of standard triple drug combinations. Cobicistat does not offer significant safety advantages over ritonavir as a pharmacokinetic booster.
Conclusions
For continued scale-up of antiretroviral treatment in low- and middle-income countries, use of first-line triple combinations including efavirenz 600 mg once daily is supported by the largest evidence base. Additional studies are underway to evaluate new treatments in key populations, and these results may justify changes to these recommendations.
doi:10.7448/IAS.19.1.20504
PMCID: PMC4740352  PMID: 26842728
antiretroviral treatment; Universal Access; nucleoside analogues; integrase inhibitors; protease inhibitors; non-nucleosides; pregnancy; tuberculosis
7.  Second European Round Table on the Future Management of HIV 
Journal of Virus Eradication  null;1(3):211-220.
Abstract
The Second European Round Table on the Future Management of HIV took place in Barcelona, 10–11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation.
An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects.
PMCID: PMC4946744  PMID: 27482415
HIV-1; primary HIV-1 infection; HIV-1 latency; HIV reservoir; inflammation; ART; pharmacokinetics; animal models; gene therapy; HIV-1 cure
8.  Patient-Reported Symptoms Over 48 Weeks in a Randomized, Open-Label, Phase IIIb Non-Inferiority Trial of Adults with HIV Switching to Co-Formulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF versus Continuation of Non-Nucleoside Reverse Transcriptase Inhibitor with Emtricitabine and Tenofovir DF 
The Patient  2015;8(4):359-371.
Background
Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; Stribild®) is a guideline-recommended regimen for HIV treatment-naïve patients and a switch option for virologically suppressed patients.
Objective
The purpose of this analysis was to understand how HIV patients’ symptoms change after switching to Stribild® versus continuing a regimen consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir disoproxil fumarate.
Methods
A secondary analysis was conducted of the STRATEGY-NNRTI study (GS-US-236-0121), a randomized, open-label, phase IIIb trial of HIV-infected adults who were taking an NNRTI plus FTC/TDF and were randomly assigned (2:1) either to Stribild® (‘switch’) or to continue on their existing regimen (‘no-switch’). Logistic regressions and longitudinal modeling were conducted to evaluate the relationship of treatment with bothersome symptoms. These models adjusted for age, sex, race, number of bothersome symptoms at baseline, Veterans Aging Cohort Study Risk (VACS) Index score, years since HIV diagnosis, and first antiretroviral therapy use, NNRTI type, serious mental illness, and baseline depression and health-related quality of life (HRQL) scores.
Results
At baseline, the prevalence of nightmares, vivid dreams, weird/intense dreams, muscle aches/joint pain, and fevers/chills/sweats was greater in the switch group. The prevalence of nightmare, vivid dreams, weird/intense dreams, dizzy/lightheadedness, fatigue/loss of energy, and pain/numbness/tingling in hands/feet deceased in the switch group at week 4, and these benefits were maintained over time. Nervous/anxious, drowsiness, trouble remembering, off balance, and body changes decreased in the switch group at week 4 but were not maintained over time. Difficulty sleeping, diarrhea/loose bowels, and bloating did not differ in prevalence at week 4 or 48, but longitudinal models suggested differences between groups over time. HRQL did not differ between groups and was unchanged over time.
Conclusions
In this study sample, a switch to co-formulated EVG/COBI/FTC/TDF was associated with significant persistent improvements in six patient-reported HIV symptoms.
Electronic supplementary material
The online version of this article (doi:10.1007/s40271-015-0129-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s40271-015-0129-9
PMCID: PMC4529476  PMID: 26045359
9.  An update to the HIV-TRePS system: the development of new computational models that do not require a genotype to predict HIV treatment outcomes 
Objectives
The optimal individualized selection of antiretroviral drugs in resource-limited settings is challenging because of the limited availability of drugs and genotyping. Here we describe the development of the latest computational models to predict the response to combination antiretroviral therapy without a genotype, for potential use in such settings.
Methods
Random forest models were trained to predict the probability of a virological response to therapy (<50 copies HIV RNA/mL) following virological failure using the following data from 22 567 treatment-change episodes including 1090 from southern Africa: baseline viral load and CD4 cell count, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. The models were assessed during cross-validation and with an independent global test set of 1000 cases including 100 from southern Africa. The models' accuracy [area under the receiver-operating characteristic curve (AUC)] was evaluated and compared with genotyping using rules-based interpretation systems for those cases with genotypes available.
Results
The models achieved AUCs of 0.79–0.84 (mean 0.82) during cross-validation, 0.80 with the global test set and 0.78 with the southern African subset. The AUCs were significantly lower (0.56–0.57) for genotyping.
Conclusions
The models predicted virological response to HIV therapy without a genotype as accurately as previous models that included a genotype. They were accurate for cases from southern Africa and significantly more accurate than genotyping. These models will be accessible via the online treatment support tool HIV-TRePS and have the potential to help optimize antiretroviral therapy in resource-limited settings where genotyping is not generally available.
doi:10.1093/jac/dkt447
PMCID: PMC3956369  PMID: 24275116
antiretroviral therapy; resource-limited settings; genotyping
10.  Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients 
Drugs in R&D  2015;15(1):141-153.
Background
Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations.
Objective
To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients.
Methods
Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1–7 and 1000/100 mg BID on days 8–14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia’s formula (∆QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days.
Results
The mean maximum ∆QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcFdense ≥30 ms (on day 10); the highest mean ∆QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated.
Conclusion
Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment.
doi:10.1007/s40268-015-0087-7
PMCID: PMC4359187  PMID: 25742730
11.  Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients 
Drugs in R&D  2015;15(1):141-153.
Background
Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations.
Objective
To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients.
Methods
Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1–7 and 1000/100 mg BID on days 8–14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia’s formula (∆QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days.
Results
The mean maximum ∆QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcFdense ≥30 ms (on day 10); the highest mean ∆QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated.
Conclusion
Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment.
doi:10.1007/s40268-015-0087-7
PMCID: PMC4359187  PMID: 25742730
12.  Large disparities in HIV treatment cascades between eight European and high-income countries – analysis of break points 
Journal of the International AIDS Society  2014;17(4Suppl 3):19507.
Introduction
Patients on antiretroviral treatment with undetectable HIV RNA levels have a significantly lower risk of clinical disease progression and onward HIV transmission. This study aimed to estimate and compare the percentage of all HIV-positive people who are diagnosed, are linked to care, are taking antiretroviral treatment and have undetectable HIV RNA, in eight European and high-income countries: the United States, the United Kingdom, France, the Netherlands, Denmark, Australia, British Columbia (Canada) and Georgia.
Materials and Methods
For each country, the number of people in five key stages of the HIV treatment cascade was collected: 1. HIV infected, 2. Known to be HIV positive, 3. Linked to care, 4. Taking antiretroviral treatment, and 5. Having undetectable HIV RNA. Estimates were extracted from national reports [1–3], the UNAIDS database, conference proceedings [4] and peer-reviewed articles [5–7]. The quality of the estimates and reporting methods were assessed individually for each country, with selection criteria such as availability of nationwide database and routinely collected data. Treatment cascades were constructed using estimates from 2010 to 2012.
Results
As shown in Table 1, the percentage of all infected people with undetectable HIV RNA ranged from 20% in Georgia to 59% in Denmark. Of the high-income countries, the United States has the lowest percentage of individuals with undetectable viral load (25% to median 52%), associated with the highest HIV incidence rate (15.30 per 100,000 to median 6.07 per 100,000). The pattern of the cascades differed between countries: in the United States, there is a fall from 66% to 33% (−33%) between linkage to care and start of antiretroviral treatment. However, in Georgia, the greatest loss in continuum was zat diagnosis, with 48% of undiagnosed HIV-positive individuals.
Conclusions
There are great disparities among European and high-income countries in the percentage of HIV-positive individual with undetectable HIV RNA. Furthermore, the treatment cascades show different key break points, underlying inequalities in HIV care between countries.
doi:10.7448/IAS.17.4.19507
PMCID: PMC4224795  PMID: 25394016
13.  Acceptance rate of clinical study endpoints and adequacy of source documentation: experience from clinical study endpoint review in NEAT001/ANRS143 
Journal of the International AIDS Society  2014;17(4Suppl 3):19572.
Introduction
NEAT001/ANRS143 was an open-label, randomized, non-inferiority study comparing raltegravir+darunavir/r(RGV+DRV/r) vs. tenofovir/emtricitabine+darunavir/r (TDF/FTC+DRV/r) in HIV-infected antiretroviral naïve adults. Primary efficacy outcome was a composite of virological and clinical events by week 96.
Materials and Methods
Clinical trial units collected and translated supporting documentation (SD) related to the investigator-reported events. A coordinator checked events and SD for consistency and completeness. The Endpoint Review Committee (ERC) determined if clinical events met pre-defined diagnostic criteria in categories “confirmed” or “probable”. The ERC of 12 experienced, independent clinicians served in groups of three conducting individual reviews in writing, blinded to treatment arm. Differences of opinion were adjudicated in a second review by direct dialogue between reviewers. “Confirmed” events required adequate SD like laboratory, radiographic or pathology diagnostic reports. “Probable” events were typically based on clinical criteria.
Results
Of the 164 serious and 3,964 adverse events reported in the study, 133 qualified for endpoint review, for a total of 153 adjudications:
Sixty of 111 per protocol endpoints were confirmed (n=53) or probable (n=7), which equals an acceptance rate of 54%. In two confirmed cases, SD was partly adequate and evaluation uncertain. Of 51 rejected events, 13 had insufficient SD, two were recurrent events. The rate of rejected events was comparable between treatments with 41% rejected events in the RGV+DRV/r arm compared to 52% in the TDF/FTC+DRV/r arm. The IRIS acceptance rate was low (3 of 18), demonstrating the difference in perception of IRIS in daily patient management and the stricter protocol definition.
Conclusions
Blinded endpoint review prevented unacceptably high false positive event rates documenting that real-time ascertainment of clinical endpoints is crucial for appropriateness of the overall results. Non-confirmed events jeopardize the statistical power in this and probably all kinds of clinical studies. The rejection rate was not indicative of poor study conduct – on the contrary over-reporting prevented missing events, which would have adversely impacted the trial. Adequacy of SD and investigator training on possible differences in event criteria in daily pragmatic clinical management compared to protocol defined criteria is essential.
doi:10.7448/IAS.17.4.19572
PMCID: PMC4224823  PMID: 25394079
14.  Predicted savings to the UK National Health Service from switching to generic antiretrovirals, 2014–2018 
Journal of the International AIDS Society  2014;17(4Suppl 3):19497.
Introduction
In other disease areas, generic drugs are normally used after patent expiry. Patents on zidovudine, lamivudine, nevirapine and efavirenz have already expired. Patents will expire for abacavir in late 2014, lopinavir/r in 2016, and tenofovir, darunavir and atazanavir in 2017. However, patents on single-tablet regimens do not expire until after 2026.
Methods
The number of people taking each antiretroviral in the UK was estimated from 23,655 individuals in the UK CHIC cohort (2012 database). Costs of patented drugs were taken from the British National Formulary database, assuming a 30% discount. Costs of generic antiretrovirals were estimated using an 80% discount from patented prices, or actual costs where available. Two options were analysed: 1 – all patients use single-tablet regimens and patented versions of drugs; prices remain stable over time; 2 – all people switch from patented to generic drugs when available, after patent expiry (dates shown above).
Results
There were an estimated 67,000 people taking antiretrovirals in the UK in 2014, estimated to rise by 8% per year until 2018 (in line with previous rises). The most widely used antiretrovirals in the CHIC cohort were tenofovir (TDF) (75%), emtricitabine (FTC) (69%), efavirenz (EFV) (39%), lamivudine (3TC) (23%), abacavir (ABC) (18%), darunavir (DRV) (21%) and atazanavir (ATV) (16%). The predicted annual UK cost of generic ABC/3TC/EFV (three generic tablets once daily) was £1018 per person-year. Costs of patented single-tablet regimens ranged from £5000 to £7500 per person-year. Assuming continued use of patented antiretrovirals in the UK, the predicted total national costs of antiretroviral treatment were predicted to rise from £425 million in 2014 to £459 m in 2015, £495 m in 2016, £536 m in 2017 and £578 m in 2018. With a 100% switch to generics, total predicted costs were £337 m in 2014, £364 m in 2015, £382 m in 2016, £144 m in 2017 and £169 m in 2018. The total predicted saving over five years from a switch to generics was £1.1 billion.
Conclusions
Systematic switching from patented to generic antiretrovirals could potentially save approximately £1.1 billion in the UK over the next five years, compared with continued use of patented versions: this money could be spent on urgently needed HIV prevention programmes. Similar savings are feasible for other European countries, given parallel patent expiry dates. More detailed economic evaluation is required to show when patented single-tablet regimens provide value for money, compared to bioequivalent generic versions of 3–4 pills once daily.
doi:10.7448/IAS.17.4.19497
PMCID: PMC4224875  PMID: 25394006
15.  Should the dose of tenofovir be reduced to 200–250 mg/day, when combined with protease inhibitors? 
Journal of the International AIDS Society  2014;17(4Suppl 3):19583.
Introduction
The approved dose of tenofovir disproxil fumarate, 300 mg once daily, was established in clinical trials in combination with efavirenz, which does not significantly affect tenofovir concentrations. Combining tenofovir with lopinavir/r, darunavir/r or atazanavir/r increases tenofovir concentrations, which could raise the risk of renal adverse events. Newly approved tenofovir tablets are available at lower strength (200 or 250 mg) for use in paediatrics.
Methods
A literature search was used to assess the effects of lopinavir/r, darunavir/r and atazanavir/r on tenofovir plasma Cmax, AUC and Cmin (Geometric Mean Ratio and 90% confidence intervals). Assuming linear dose-proportional pharmacokinetics (as observed in dose-ranging studies), the 250 mg tablet was predicted to achieve plasma concentrations 17% lower than the 300 mg dose, and the 200 mg tablet to achieve plasma levels 33% lower. Effects on tenofovir plasma Cmax, AUC and Cmin concentrations were assessed for combined dosing of each protease inhibitor with 250 or 200 mg daily doses of tenofovir, versus standard dose tenofovir (300 mg daily) without protease inhibitors.
Results
In drug-drug interaction studies, lopinavir/ritonavir significantly increased tenofovir Cmax, AUC and Cmin. Effects of each PI on tenofovir Cmin were greater than effects on Cmax or AUC. Using a 250 mg paediatric dose of tenofovir with lopinavir/ritonavir, tenofovir Cmin was predicted to remain higher than tenofovir 300 mg used with efavirenz (GMR=1.26, 95% CI 1.14–1.38). Similar results were observed for use of tenofovir 250 mg with atazanavir/ritonavir (GMR=1.07, 95% CI 1.01–1.13) and with darunavir/ritonavir (GMR=1.14, 95% CI 0.99–1.31). Predicted tenofovir AUC levels for the 250 mg dose with protease inhibitors were all within the bioequivalence range, relative to use with efavirenz. Using a 200 mg paediatric dose of tenofovir with lopinavir/ritonavir, the tenofovir Cmin was predicted to be bioequivalent to tenofovir 300 mg used with efavirenz (GMR=1.02, 95% CI 0.92–1.11). Similar results were observed for use of tenofovir 200 mg with atazanavir/ritonavir (GMR=0.86, 95% CI 0.82–0.91) and with darunavir/ritonavir (GMR=0.92, 95% CI 0.80–1.05). All three results were within the bioequivalence limits of 0.8–1.25.
Conclusions
Use of approved paediatric doses of tenofovir (200–250 mg once daily) in combination with lopinavir/r,darunavir/r or atazanavir/r could compensate for known drug interactions. This dose modification could potentially improve renal safety.
doi:10.7448/IAS.17.4.19583
PMCID: PMC4224934  PMID: 25394089
16.  Detection of resistance mutations and CD4 slopes in individuals experiencing sustained virological failure 
Journal of the International AIDS Society  2014;17(4Suppl 3):19737.
Introduction
Several resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance mutations on CD4 slopes in patients undergoing episodes of viral failure.
Materials and Methods
Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test during the episode were included. Mutations were identified using the IAS-US (2013) list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log-scale), risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope.
Results
A total of 2731 patients experiencing a median of 1 (range 1–4) episodes were included in this analysis. The prevalence of any resistance per episode was 88.4%; NNRTI resistance was most common (78.5%). Overall, CD4 counts declined by 17.1 (−19.7; −14.5) cells per year; this decline was less marked with partial viral suppression (current HIV RNA more than 1.5 log below the setpoint; p=0.01). In multivariable models adjusting for viral load, CD4 decline was slower during episodes with detected resistance compared to episodes without detected resistance (21.0 cells/year less, 95% CI 11.75–30.31, p<0.001). Among those with more than one resistance mutation, there was only weak evidence that class-specific mutations had any effect on the CD4 slope (Table 1). The effects of individual mutations (incl. M184V) were explored, but none were significantly associated with the CD4 slope; for these comparisons, a Bonferroni-corrected p-value level was 0.003.
Conclusions
In our study population, detected resistance was associated with slightly less steep CD4 declines. This may be due to a biological effect of resistance on CD4 slopes, or other unmeasured factors such as poor adherence among individuals without resistance. Among individuals with detected drug resistance, we found no evidence suggesting that the presence of individual mutations was associated with beneficial CD4 slope changes.
doi:10.7448/IAS.17.4.19737
PMCID: PMC4225350  PMID: 25397482
17.  Transmitted antiretroviral drug resistance in treatment naïve HIV-infected persons in London in 2011 to 2013 
Journal of the International AIDS Society  2014;17(4Suppl 3):19747.
Introduction
Previously published UK data on HIV transmitted drug resistance (TDR) shows that it ranges between 3 and 9.4% [1,2]. However, there are no recent data from populations where HIV transmission rates are increasing. The aim of this study was to assess the prevalence of TDR in untreated HIV-infected individuals attending three HIV specialist clinics under the HIV Directorate, Chelsea and Westminster Hospital and based throughout London – the Kobler Clinic, 56 Dean Street and West London Centre for Sexual Health.
Methods
We included all patients with a HIV diagnosis, no history of antiretroviral therapy (ART) intake, attending one of the three clinics (Kobler (K), 56 Dean Street (DS) and West London (WL)), between 2011 and 2013 who started antiretrovirals. Reverse transcriptase (RT) and protease region sequencing was performed using Vircotype virtual phenotype resistance analysis. Drug resistance mutations were identified according to Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu/).
Results
Among 1705 HIV-1-infected patients enrolled in the study, 1252 were males (919 were MSM), 107 were females and 346 had no gender recorded. Ethnicity was 51.1% white British/Irish/other, 6.1% African, 2.1% Caribbean, 2.8% Asian, 1.3% Indian/Pakistani/Bangladeshi, 4.2%, other, 3.2% not stated, and 29.2% unknown. 547 were from K (84.3% males, 48.3% MSM), 826 were from DS (84.3% males, 71.9% MSM), and 109 from WL (87.2% males, 56.0% MSM), 223 from other sites not specified. 77.5% (1321 of 1705) of patients had baseline viral resistance testing performed. Prevalence of primary resistance in those with a baseline viral resistance test was 13.5% overall: 19.3% in K, 14.9% in DS, and 14.7% in WL. The most common mutations detected were: NRTI: 184V, 215F, 41L; NNRTI 103N, 179D, 90I; PI 90M, 46I, and 82A. Among patients who tested with TDR, 79.1% had one single mutation, 18.7% and 2.2% exhibited dual or triple class-resistant viruses, respectively.
Conclusions
This study across a large HIV Medicine Directorate reported an overall TDR prevalence which is higher than that previously published and with significant rates of NNRTI resistance at baseline.
doi:10.7448/IAS.17.4.19747
PMCID: PMC4225370  PMID: 25397492
18.  Switch to Stribild versus continuation of NVP or RPV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY-NNRTI subgroup analysis 
Journal of the International AIDS Society  2014;17(4Suppl 3):19793.
Introduction
Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults [1]. We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects.
Materials and Methods
Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by non-EFV NNRTI use (NVP [74]; RPV [19]; etravirine [3]) at screening was pre-specified.
Results
The mITT population included 433 subjects who were randomized and treated. In the non-EFV NNRTI subgroup, 59 switched to STB; 37 continued a non-EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non-EFV NNRTI maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non-EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB versus non-EFV NNRTI group; median changes (mL/min) at week 48: −9.1 versus −1.4. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: −15 to 15) at week 4 (median: 14 vs 11; p=0.047) and week 24 (median: 14 vs 12.5; p=0.038).
Conclusions
In this small group of virologically suppressed subjects, switch to STB vs continuation of NVP or RPV with FTC/TDF was safe, well-tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.
doi:10.7448/IAS.17.4.19793
PMCID: PMC4225425  PMID: 25397537
19.  Protease mutations emerging on darunavir in protease inhibitor-naïve and experienced patients in the UK 
Journal of the International AIDS Society  2014;17(4Suppl 3):19739.
Introduction
Darunavir (DRV) is a preferred agent in treatment guidelines for ART-naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance-associated mutations (RAMs) are recognized by IAS-USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short-term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.
Materials and Methods
The UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV-containing regimen. Patients were included if they had a “baseline” resistance test, prior to DRV exposure, and a “repeat” test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.
Results
A total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI-naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI-naïve and 20 (13.4%) PI-experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI-naïve patients, and in 7 (4.7%) PI-experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI-naïve patients and 296 days for PI-experienced.
Conclusions
PI-experienced patients had a greater prevalence of DRV RAMs at baseline than PI-naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.
doi:10.7448/IAS.17.4.19739
PMCID: PMC4225433  PMID: 25397484
20.  Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals 
PLoS ONE  2014;9(1):e87334.
Background
The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown.
Methods
Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation).
Results
Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8+ T cells were indistinguishable between the two arms and did not change over time between the groups.
Conclusions
Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.
doi:10.1371/journal.pone.0087334
PMCID: PMC3903883  PMID: 24475275
21.  Potential Impact of a Free Online HIV Treatment Response Prediction System for Reducing Virological Failures and Drug Costs after Antiretroviral Therapy Failure in a Resource-Limited Setting 
BioMed Research International  2013;2013:579741.
Objective. Antiretroviral drug selection in resource-limited settings is often dictated by strict protocols as part of a public health strategy. The objective of this retrospective study was to examine if the HIV-TRePS online treatment prediction tool could help reduce treatment failure and drug costs in such settings. Methods. The HIV-TRePS computational models were used to predict the probability of response to therapy for 206 cases of treatment change following failure in India. The models were used to identify alternative locally available 3-drug regimens, which were predicted to be effective. The costs of these regimens were compared to those actually used in the clinic. Results. The models predicted the responses to treatment of the cases with an accuracy of 0.64. The models identified alternative drug regimens that were predicted to result in improved virological response and lower costs than those used in the clinic in 85% of the cases. The average annual cost saving was $364 USD per year (41%). Conclusions. Computational models that do not require a genotype can predict and potentially avoid treatment failure and may reduce therapy costs. The use of such a system to guide therapeutic decision-making could confer health economic benefits in resource-limited settings.
doi:10.1155/2013/579741
PMCID: PMC3794568  PMID: 24175292
22.  Pharmacokinetic analysis to assess forgiveness of boosted saquinavir regimens for missed or late dosing 
Objectives
One potential concern of once-daily protease inhibitor administration is low trough concentrations and ultimately the ‘forgiveness’ or robustness in comparison with the originally licensed twice-daily dose. To give an estimation of ‘forgiveness’, we determined the length of time plasma drug concentrations were below target in HIV-infected patients receiving saquinavir/ritonavir regimens.
Methods
Seventy-seven pharmacokinetic profiles (saquinavir/ritonavir 1000/100 mg twice daily, n = 34; 1600/100 mg once daily, n = 26; 2000/100 mg once daily, n = 17) from five studies were combined, presented as twice- and once-daily percentiles (P10–P90) and compared. At percentiles where trough concentrations fell below the alleged minimum effective concentration (MEC; 100 ng/mL), the length of time below MEC was determined.
Results
Saquinavir concentrations were below MEC at P10 for 0.7 h for twice-daily saquinavir/ritonavir when compared with 8.6 and 6.6 h for 1600/100 and 2000/100 mg once daily, respectively. At P25, 1600/100 mg once daily produced suboptimal concentrations for 5.5 h in contrast to 0.5 h for 2000/100 mg once daily.
Conclusions
Here, we provide substantive data that indicate once-daily saquinavir, in particular 1600/100 mg, is not as robust as the twice-daily regimen based on a population of UK patients; this raises concern over late or missed doses. However, pharmacokinetic data can only ever be a guide to the impact on long-term efficacy.
doi:10.1093/jac/dkn187
PMCID: PMC3672987  PMID: 18467305
HIV; pharmacokinetics; once daily; robustness
23.  Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals 
Objectives
The aim of this study was to develop and validate a population pharmacokinetic model in order to describe ritonavir-boosted saquinavir concentrations dosed twice and once daily in human immunodeficiency virus (HIV)-infected patients from the UK, Uganda and Thailand and to identify factors that may influence saquinavir pharmacokinetics.
Methods
Pharmacokinetic data from 10 clinical studies were combined. Non-linear mixed effects modelling (NONMEM version V) was applied to determine the saquinavir pharmacokinetic parameters, interindividual/interoccasion variability (IIV/IOV) and residual error. Various covariates potentially related to saquinavir pharmacokinetics were explored, and the final model was validated by means of 95% prediction interval and testing the predictive performance of the model with data not included in the model-building process.
Results
Ninety-seven patients were included from the UK (n = 52), Uganda (n = 18) and Thailand (n = 27), contributing 347 saquinavir profiles (1–14 profiles per patient). A one-compartment model with zero-order absorption and lag-time best described the data with IIV/IOV on apparent oral clearance (CL/F) and volume of distribution (V/F) and with IIV on duration and absorption lag-time. The ritonavir area under the curve over the dosing interval was significantly associated with saquinavir CL/F and V/F. A typical patient from the UK had ~1.5- and 3-fold higher saquinavir CL/F compared with patients from Uganda (89.0 versus 49.8 L/h) and Thailand (89.0 versus 26.7 L/h), respectively.
Conclusions
A model to characterize ritonavir-boosted saquinavir pharmacokinetics in HIV-infected adults has been developed and validated. The model could be used for dosage adaptation following therapeutic drug monitoring and to assess patients’ suitability for once-daily boosted saquinavir therapy.
doi:10.1093/jac/dkn399
PMCID: PMC3597129  PMID: 18824460
NONMEM; UK; Uganda; Thailand; variability
24.  Lower Healthcare Costs Associated with the Use of a Single-Pill ARV Regimen in the UK, 2004–2008 
PLoS ONE  2012;7(10):e47376.
Aim
Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months.
Methods
Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996–2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively.
Results
All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens.
Conclusion
The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.
doi:10.1371/journal.pone.0047376
PMCID: PMC3484120  PMID: 23118869
25.  The Ethics of Switch/Simplify in Antiretroviral Trials: Non-Inferior or Just Inferior? 
PLoS Medicine  2012;9(7):e1001240.
Using the SWITCHMRK and MONET trials as examples, Andrew Carr and colleagues question the ethics and motives of switch or simplification trials of anti-retroviral therapy.
doi:10.1371/journal.pmed.1001240
PMCID: PMC3398965  PMID: 22815652

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