bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistance: what is new and on the horizon, and a time to teach old dogs new tricks?
Authors: Schapiro Jonathan
Published: November 2014

Understanding HIV drug resistance has played a key role in the success of antiretroviral therapy. This knowledge allowed for the prediction of resistance evolution when a specific drug or combinations of drugs were administered, informing strategies implemented for initial and subsequent drug regimens. Resistance testing of individual patients detects transmitted as well as acquired drug resistance as a result of treatment failure, leading to improved treatment choices in drug naïve and drug experienced patients accordingly. The last two decades has seen a great deal of evolution, improvement and change in the care of HIV‐positive individuals. Much of this was aimed at preventing, reducing or minimizing the impact of HIV drug resistance. Drugs with much improved resistance characteristics were designed and gained widespread use, as well as those with superior pharmacology and toxicity profiles assisting in better adherence and far reduced failure rates. Patient management strategies and monitoring technologies were refined, and education of clinicians and patients on optimal aspects of care routinely was implemented. All these have led to a new world of HIV clinical care and require a rethinking of how best to use our knowledge of resistance and when, how and in whom to test for it. What lays ahead for HIV drug resistance in the near and distant future, and is it time to teach old dogs new tricks?
First prospective comparison of genotypic vs phenotypic tropism assays in predicting virologic responses to Maraviroc (MVC) in a phase 3 study: MODERN
Authors: Heera Jayvant , Valluri Srinivas , Craig Charles , Fang Annie , Thomas Neal , Dan Meyer Ralph , Demarest James
Published: November 2014

Introduction

MODERN (A4001095) was the first prospective phase 3 study comparing genotype vs phenotype (Trofile™) tropism assessments.

Materials and Methods

Treatment‐naïve adults with HIV‐1 RNA >1000 copies/mL were randomized 1:1 at screening to either genotype or Trofile for tropism assessment. Genotype was determined using the geno2pheno algorithm to assess triplicate HIV‐1 gp120 V3 loop sequences (plasma); false‐positive rate=10%. R5‐virus‐infected subjects were then randomized 1:1 to receive Maraviroc (MVC) 150 mg QD or Truvada 200/300 mg QD each with DRV/r 800/100 mg QD. Tropism of screening samples from enrolled subjects was also retrospectively determined using the alternate testing method. Positive predictive values (PPV) were estimated by%R5 subjects with Week 48 HIV‐1 RNA < 50 c/mL. PPV for each assay was estimated using the response rate among those randomized to that assay and using model‐based response estimates in those with R5 by that assay (at screening or retest).

Results

The observed response rate was 146/181 (80.7%) for genotype vs 160/215 (74.4%) for Trofile (stratification adjusted difference=6.9%, 95% CI 1.3% to 15%). The model‐based estimates of PPV (±SE) were 79.1% (±2.42) and 76.3% (±2.38), respectively (difference = 2.8%, 95% CI −2.1% to 7.2%). There was no difference in response rate between assays in the Truvada arm (observed difference=− 0.1%, 95% CI −6.8% to 6.6%). Most enrolled subjects had R5 results at screening using both assays (285/396 (72%)), and of these subjects, 79.3% (226/285) had HIV‐1 RNA <50 c/mL at week 48 (Table 1). The few subjects classified as non‐R5 by the alternate assay had similar virologic responses to the concordant R5 group.

Conclusion

There was a higher MVC response rate and model‐based positive predictive value with genotype compared to Trofile, but this difference did not reach statistical significance. The majority of subjects had concordant R5 tropism results. Either phenotype or genotype can effectively predict MVC response.
Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring
Authors: Yang Shang‐Ping , Liu Wen‐Chun , Lee Kuan‐Yeh , Wu Bing‐Ru , Su Yi‐Ching , Wu Pei‐Ying , Zhang Jun‐Yu , Luo Yu‐Zhen , Sun Hsin‐Yun , Chang Sui‐Yuan , Lin Shu‐Wen , Hung Chien‐Ching
Published: November 2014

Introduction

Wide inter‐patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV‐positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV‐containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)‐guided strategy to optimize the EFV dose in HIV‐positive Taiwanese patients.

Materials and Methods

The plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV‐positive adults who had received EFV‐containing cART with viral suppression (plasma HIV RNA load (PVL) <200 copies/mL). For those with EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4–12 weeks after switch using high‐performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase‐chain‐reaction restriction fragment‐length polymorphism.

Results

Between April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL <40 copies/ml; 26.4% HBsAg‐positive and 7.5% anti‐HCV‐positive) with plasma C12 efavirenz >2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62–4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53–2.33) for 64 patients who had completed follow‐up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9–57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow‐up of PVL achieved undetectable PVL (<40 copies/ml) following switch to a reduced dose of EFV after a mean observation of 13 weeks (IQR, 7–15 weeks).

Conclusions

Switch to cART containing a half tablet of EFV (1/2#) in HIV‐positive Taiwanese patients with higher plasma EFV concentrations who had achieved viral suppression could maintain successful viral suppression with the guidance of TDM.
Analysis of neurocognitive function and CNS endpoints in the PROTEA trial: darunavir/ritonavir with or without nucleoside analogues
Authors: Clarke Amanda , Johanssen Veronika , Gerstoft Jan , Clotet Bonaventura , Ripamonti Diego , Murungi Andrew , Bicer Ceyhun , Blanca Hadacek Maria , Moecklinghoff Christiane
Published: November 2014

Introduction

During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear.

Methods

A total of 273 patients with HIV RNA <50 copies/mL for over 24 weeks on current antiretrovirals randomized to darunavir/ritonavir (DRV/r) 800/100 mg once‐daily, either as monotherapy (n=137) or with 2NRTIs (n=136). Neurocognitive function was evaluated in all patients by the Hopkins Verbal Learning Tests, the Colour Trail Tests and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ‐5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub‐study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse events related to the CNS were collected at each visit.

Results

Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48, there was no difference between the treatment arms for the five combined domains of the neurocognitive score. At Week 48, the percentage of patients with an abnormal neurocognitive score among the five domains was 12.2% for DRV/r monotherapy and 14.9% for triple therapy. However, one patient on DRV/r monotherapy with a CD4 nadir of 17 cells/µL was hospitalized with HIV encephalomyelitis at Week 24, with HIV RNA 2500 copies/mL in the CSF and 125 copies/mL in the plasma. Symptoms resolved after intensification with high dose zidovudine. A second patient on DRV/r monotherapy with CD4 nadir of 166 cells/µL had a rise in HIV RNA in CSF from <40 copies/mL at baseline to 654 copies/mL at Week 48, with concurrent plasma HIV RNA of 77 copies/mL.

Conclusions

In this study for patients with HIV RNA <50 copies/mL at baseline, there was no difference in neurocognitive function between the treatment arms. However two patients on PI monotherapy with CD4 nadir <200 cells/µL developed viraemia in both CSF and plasma, with one symptomatic case. DRV/r monotherapy should be used with caution in patients with nadir CD4 counts below 200 cells/µL.
Evolution of Framingham cardiovascular risk score in HIV‐infected patients initiating EFV‐ and LPV/r‐based HAART in a Latin American cohort
Authors: Cecchini Diego , Ines Mattioli Maria , Cassetti Julia , Chan Debora , Cassetti Isabel
Published: November 2014

Introduction

Epidemiological studies suggest that some antiretroviral drugs may contribute to increase cardiovascular risk in HIV‐infected patients. However, data from Latin American countries are limited, as impact of HAART on cardiovascular risk remains understudied. In this context, we aimed to evaluate if 10‐year Framingham Cardiovascular Risk Score (FCRS) increases in patients following exposure to EFV‐ and LPV/r‐based HAART in a Latin American cohort.

Materials and Methods

Retrospective 48‐week cohort study. We reviewed clinical charts of randomly selected samples of patients initiating (according to national guidelines) EFV first‐line HAART and LPV/r first‐ or second‐line (but first PI‐based) HAART assisted at a reference HIV centre in Buenos Aires, Argentina (period 2004–2012). Each patient could only be included in one arm. FCRS was calculated according to National Institutes of Health risk assessment tool (http://cvdrisk.nhlbi.nih.gov/).

Results

A total of 357 patients were included: 249 in EFV arm and 108 in LPV/r arm (80 as first line and 28 as second line, but first PI‐based HAART). Baseline characteristics (median, interquartile range): age, 38 (33–45) years; male, 247 (69%); viral load, 98200 (20550–306000) copies/mL; CD4 T‐cell count, 115 (60–175) cel/µL; total cholesterol, 159 (135–194) mg/dL; HDL: 39 (31–41) mg/dL; LDL: 94 (72–123) mg/dL; current smoker, 29%; on antihypertensive drugs: 14 (4%), diabetic: 4 (1%). Most frequent accompanying nucleoside reverse transcriptase inhibitors (NRTIs) were 3TC (92%) and zidovudine (AZT; 76%). Baseline FCRS was low, moderate and high for 93%, 7% and 0% of patients on EFV arm and 96.7%, 1.7% and 1.7% on LPV/r arm. On EFV arm, an increase in FCRS category (low to moderate or moderate to high) was observed in 1 patient (0.9%) at 24 weeks and 6 (5,6%) at 48 weeks; 5 (4.7%) decreased category. On LPV/r arm no one varied FCRS category at 24 weeks and 2 (3.4%) increased from low to moderate at 48 weeks (no patient decreased FCRS category). Cumulative incidence of overall cardiovascular events was 1.6% on EFV and 1.8% on LPV/r arms respectively. Probability of increasing FCRS category or having a cardiovascular event did not differ between arms at a significance level of 5%.

Conclusions

Probability of increasing FCRS category and cardiovascular events was low and similar in patients exposed to EFV versus LPV/r‐based HAART in a Latin American cohort. ClinicalTrials.gov Identifier: NCT01705873.
Impact of NRTI backbone on renal, bone and cardiovascular markers in HIV‐infected individuals receiving a boosted protease inhibitor
Authors: Barber Tristan , Hill Andrew , Jagjit Singh Gurmit , Boffito Marta , Nelson Mark , Moyle Graeme
Published: November 2014

Introduction

We have previously shown in the SSAT 044 study that unconjugated hyperbilirubinaemia in subjects receiving a boosted protease inhibitor (PI/r) has limited impact on renal, cardiovascular (CV) and bone biomarkers, as well as on neurocognitive performance, relative to those receiving PI/r with a normal bilirubin. We present here a secondary analysis comparing markers in those receiving abacavir‐ vs tenofovir‐ based antiretroviral therapy (ART).

Materials and Methods

This cross‐sectional study included 101 HIV‐1 infected individuals stable (HIV RNA<50 cps/ml, >6 months) on antiretroviral regimens including tenofovir (TDF)/emtricitabine or abacavir/lamivudine plus a ritonavir boosted PI.

Results

Forty‐three subjects had normal bilirubin (NBR) levels and 35 had high bilirubin (>2.5 times upper limit); the remaining 23 patients had intermediate bilirubin levels or violated the protocol. The mean age of participants was 48 years; 93% were male and 84% Caucasian; 22 received ABC‐based therapy and 78 TDF. No differences were seen in cardiovascular markers: Framingham (10‐year risk % median, IQR): ABC 8.1, 5.6–15.3; TDF 9.5, 4.8–13.4 (p=ns); pulse wave velocity and carotid intimal thickness also showed no significant differences. No differences were seen in bone parameters: Calcaneal Stiffness Index (median score, IQR): ABC −0.5, −0.8 to 0.8; TDF −0.5, 1.4–0.4 (p=ns); 10 year FRAX score (% median, IQR): ABC 5.0, 2.4–6.2; TDF 3.6, 2.5–5.8 (p=ns). There were differences in renal parameters as shown in Table 1. We show statistically significant differences in urine protein/creatinine ratio (uPCR) (10 vs 7; p=0.004) and urine albumin/creatinine ratio (uACR) (15 vs 8; p=0.002), with both being higher in the TDF group.

Conclusions

Tenofovir use is associated with excess loss of proteins including those typically resorbed in the renal tubule. Abacavir use was not associated with an increase in biomarkers of CV risk or vascular dysfunction.
Attitudes of serodiscordant couples towards antiretroviral‐based HIV prevention strategies in Kenya: a qualitative study
Authors: Fowler Nikola , Arkell Paul , Abouyannis Michael , James Catherine , Roberts Lesley
Published: November 2014

Introduction

Transmission in serodiscordant couples (SDCs) accounts for approximately half of all new HIV infections, both in Kenya and the wider sub‐Saharan region [1]. With evidence to suggest inconsistent condom use within this population [2], the World Health Organization has recommended two new methods of HIV prevention for SDCs: Treatment as Prevention (TasP) and Pre‐Exposure Prophylaxis (PrEP). However, there has been little research about the attitudes of SDCs towards these strategies [3, 4]; knowledge that is paramount for successfully predicting the acceptability and efficacy of each method, as well as for informing decisions regarding HIV policy changes in Kenya.

Methods

An exploratory, qualitative study was conducted in the Muhoroni constituency of Nyando district, Kenya from January to March 2013. Purposive sampling was predominately used to recruit 21 HIV‐positive and 17 HIV‐negative individuals in a serodiscordant relationship from four hospitals and health centres. During face‐to‐face semi‐structured interviews, topic guides were used to elicit information about participants’ attitudes and preferences towards TasP and PrEP. Collected data underwent framework analysis, allowing the development of overarching categories, sub‐themes and inductive interpretation.

Results

The majority of participants, irrespective of gender and HIV status, found TasP more acceptable than PrEP. A key factor influencing this decision was HIV‐negative participants’ limited motivation to take and adhere to antiretrovirals (ARVs), primarily due to a predominantly external health locus of control, a lack of cultural acceptance of prophylactic medication and concerns about side effects. In addition to this, the likely health improvements TasP offers HIV‐positive partners, as well as the attitude that the sick individual should be the first to receive HIV medication, also contributed to this conclusion. Issues of risk compensation were raised, with some HIV‐negative partners indicating a desire to stop using condoms if ARV‐based prevention methods were available.

Conclusions

Findings from the study indicate that TasP may represent a more viable approach to HIV prevention in Kenya than PrEP. Couples’ preferences, however, may differ depending on local attitudes towards prophylaxis and health locus of control.
Prevalence of low bone mineral density among HIV patients on long‐term suppressive antiretroviral therapy in resource limited setting of western India
Authors: Dravid Ameet , Kulkarni Milind , Borkar Amit , Dhande Sachin
Published: November 2014

Introduction

Bone mineral density (BMD) assessment in HIV patients is sparsely done in resource limited settings.

Materials and Methods

We conducted a cross‐sectional study of BMD amongst HIV patients following up in our clinic from 1 June to 1 December 2013 by performing dual‐energy X‐ray absorptiometry scan (Lunar Prodigy Advanced DXA System, GE Healthcare) of lumbar spine and hip. Patients on long term (≥12 months), virologically suppressive antiretroviral therapy (ART) were included. Patients who were ART naïve were included as control population. Virologic failures were excluded. Low BMD was defined by WHO T‐score criteria (normal: T score ≥−1;osteopenia: T score between −1 and −2.5 SD; osteoporosis: T score ≤−2.5 SD). Baseline risk factors associated with low BMD like age, low BMI, lipoatrophy, diabetes mellitus, current smoking, current alcohol intake, steroid exposure and menopause were recorded. ART‐related factors associated with low BMD like ART duration, exposure to tenofovir and exposure to protease inhibitors (PI) were studied.

Results

A total of 536 patients (66% males, 496 ART experienced and 40 ART naïve) were included in this analysis. Median age was 42 years, mean BMI 23.35 kg/m2 and median CD4 count 146 cells/mm3. All ART experienced patients had plasma viral load<400 copies/ml.

Prevalence of low BMD amongst ART naive and ART experienced patients was 67% (osteopenia: 70.4%, osteoporosis: 29.6%) and 80.4% (osteopenia: 63.4%, osteoporosis: 36.6%), respectively (p=0.05). Mean T scores at lumbar spine and hip for ART naive and ART experienced patients were −1.37 and −0.9 versus −1.56 and −1.48 (p=0.05), respectively. Age, low BMI, current smoking, menopause, baseline CD4 count and exposure to ART were factors significantly associated with low overall BMD on univariate regression analysis. On multivariable logistic regression analysis age (p<0.001), low BMI (p<0.001), current smoking (0.05) and menopause (0.03) were associated with low BMD. BMI decrease of 1 kg/m2 and baseline CD4 decline of 50 cells/mm3 lead to 14% and 4% increased probability of low BMD, respectively. Choice of antiretroviral use (tenofovir vs non‐tenofovir, PI vs No PI) did not influence loss of BMD.

Conclusions

Extremely high prevalence of accelerated BMD loss amongst ART naïve and ART experienced patients in our cohort is a matter of deep concern due to its association with pathological fractures. Bone mineral loss was seen irrespective of ART used. Association of low BMD with low baseline CD4 count strengthens the case for early ART.
Acceptance rate of clinical study endpoints and adequacy of source documentation: experience from clinical study endpoint review in NEAT001/ANRS143
Authors: Berenguer Juan , Wit Ferdinand , Jansson Per O , Schwimmer Christine , Kowalska Justyna D , Saillard Juliette , Diallo Alpha , Pozniak Anton L , Raffi François , Grarup Jesper
Published: November 2014

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.
Safety of rilpivirine plus nucleoside reverse‐transcriptase inhibitors in HIV‐infected Taiwanese with a higher prevalence of hepatitis virus infection
Authors: Wu Pei‐Ying , Cheng Chien‐Yu , Luo Yu‐Zhen , Zhang Jun‐Yu , Yang Shan‐Ping , Cheng Shu‐Hsing , Hung Chien‐Ching
Published: November 2014

Introduction

Combination antiretroviral therapy (cART) containing rilpivirine plus 2 NRTIs are effective antiretroviral (ARV) regimens for ARV‐naive HIV‐infected patients who had baseline plasma HIV RNA load (PVL) <5 log10 copies/mL and as switch therapy for those with viral suppression. In this study, we aimed to assess the short‐term safety of rilpivirine‐containing regimens among HIV‐infected patients who initiated or switched to rilpivirine plus two NRTIs in Taiwan.

Materials and Methods

Between January and June 2014, medical records of all HIV‐infected patients who initiated or switched to rilpivirine plus two NRTIs, during the follow‐up were reviewed to assess the tolerance and adverse effects. Using a standardized data collection form, we recorded data of PVL and CD4 count, serologies for hepatitis B and C virus (HBV and HCV, respectively), haemogram, aminotransferases, bilirubin and serum creatinine before starting rilpivirine‐containing regimens at four weeks and every 12 weeks thereafter.

Results

During the study period, medical records of 246 patients initiated their first ARV therapy with rilpivirine‐containing regimens (n=90) or switched to rilpivirine‐containing regimen from other regimens (156). Of the 246 patients, 73.4% were men who have sex with men and 9.1% and 25.6% tested positive for HBsAg and anti‐HCV antibody, respectively. Baseline CD4 was 395 cells/mm3 (range, 2‐1581) and PVL, 2.76 log10 copies/mL (range, <1.3>7.0 log10 copies/mL). As of 10 July, 23 patients (9.3%) stopped rilpivirine‐containing regimens due to gastrointestinal upset (n=4), skin rash (2), depression (2), poor sleep (3), anaemia (4, all being with zidovudine/lamivudine), nail hyperpigmentation (1), presence of transmitted drug resistance (4), and elevated aminotransferase levels (1). The proportion of the patients with aminotransferases of fivefold or higher than the upper limit of normal (ULN) was 1.7% and 1.5% for AST and ALT, respectively, before starting rilpivirine‐containing regimens; the respective value was 1.4% and 2.4% after 12 weeks of cART.

Conclusions

Rilpivirine‐containing regimens were generally well tolerated and less than 10% of the patients had to stop rilpivirine due to various reasons. Despite a higher prevalence of chronic HBV or HCV infection, rilpivirine‐containing regimens did not cause significant changes of aminotransferases from baseline.
CSF LPV concentrations and viral load in viral suppressed patients on LPV/r monotherapy given once daily
Authors: Tiraboschi Juan , Imaz Arkaitz , Ferrer Elena , Saumoy Maria , Rozas Nerea , Maso Marga , Vila Antonia , Niubo Jordi , Podzamczer Daniel
Published: November 2014

Introduction

Plasma trough concentrations of lopinavir (LPV) given as LPV/r 800/200 mg once daily (OD) are reduced in comparison with 400/100 mg twice daily (BID). While OD dosage of LPV/r is sufficient to achieve viral suppression in plasma, data about drug penetration and viral suppression in central nervous system (CNS) is needed, mainly if LPVr is used as maintenance monotherapy strategy in selected patients. The objective of this study was to evaluate CSF HIV‐1 RNA and CSF LPV concentrations in patients receiving LPV/r monotherapy OD (LPVrMOD).

Material and Methods

This is a cross‐sectional sub‐study within a prospective, open‐label pilot simplification study to evaluate the efficacy and safety of LPV/rMOD in virologically suppressed patients previously receiving a BID LPV/r monotherapy regimen (LPV/rMBID), the “Kmon study” (NCT01581853). To assess LPV concentrations and HIV‐1 RNA in CSF, a lumbar puncture (LP) was performed in a subgroup of patients after at least one month of LPVrMOD treatment. Plasma‐paired samples of all patients were also obtained. HIV‐1 RNA was determined by real‐time PCR (limit of detection 40 copies/mL). Liquid chromatography‐tandem mass spectrometry (Tandem labs, NJ) was used to determine CSF and blood plasma LPV concentrations.

Results

Nine patients were included. Median (range) age was 48 (34–56) years, median CD4 cell count 672 (252–1,408) cells/mL, median nadir CD4 count 125 (35–537) cells/mL and 40% of subjects were HCV‐positive. Before starting LPV/rMOD median time on a LPV/r‐containing regimen and on LPV/rMBID were 9 (4–11) years and 15 (7–24) months respectively, median time with undetectable HIV viral load was 5 (3–12) years and 2 patients had a previous documented blip. LP was performed a median of 24 (8–36) weeks after starting LPV/rMOD and 24 (11–28) hours after the last LPV/rMOD dose CSF and plasma HIV RNA was 40 copies/mL in all patients. Median LPV CSF concentration was 9.78 (1.93–78.3) ng/mL, median LPV plasma concentration 1,103 (377–16,700) ng/mL and median LPV CSF/plasma ratio 0.3% (0.1–1.2).

Conclusions

No CSF viral escape was detected and LPV concentrations were above the IC50 for wtHIV‐1 (1.9 ng/mL). However, as concentrations were close to IC50 in some patients, a careful clinical follow up of patients receiving this regimen would be advisable. Larger longitudinal studies will be helpful for a better understanding of the CNS antiviral activity of LPVr monotherapy.
Should we offer routine hepatitis C antibody testing in men who have sex with men?
Authors: Ward Christopher , Lee Vincent
Published: November 2014

Introduction

There has been a significant rise in the number of HIV positive men who have sex with men (MSM) co‐infected with hepatitis C (HCV). Most infections are thought to occur through high risk sexual practices, exacerbated by drug use. Previous data has suggested no need for routine screening in HIV negative MSM. We looked at HCV antibody testing and HCV risk assessment in all MSM clinic attenders as part of a Public Health England initiative.

Materials and Methods

Routine HCV antibody testing was offered to all MSM attending a large inner city sexual health clinic from April to June 2014. Patients were asked to fill in a questionnaire assessing HCV risk. Demographic data, HIV status and STI results were collected and compared.

Results

We collected 471 HCV risk assessment questionnaires during the eight‐week period. The median age was 34 (range 18–71) and 403 (85.6%) were White British. Ten (2.1%) patients were known to be HCV positive, of which 3 were on treatment and 5 (1.1%) had cleared HCV. One hundred and forty‐nine (31.6%) patients were HIV negative, 254 (53.9%) were HIV positive and 68 (14.5%) had unknown HIV status at time of clinic visit. In the last three months 151 (32.1%) reported unprotected receptive anal intercourse, 58 (12.3%) reported group sex, 11 (2.3%) reported receptive fisting and 32 (6.8%) reported more than 10 partners. Eighty‐seven (18.5%) patients had shared notes/straws to snort drugs and 29 (6.2%) reported injecting drugs or slamming. One hundred and forty‐two (30.0%) patients reported recreational drug use in the last 12 months, with cocaine, methadrone and ketamine most popular. One hundred and fifteen (24.4%) patients reported sex under the influence of recreational drugs. There were no statistical differences between HIV positive and HIV negative patients in their risk, sexual behaviour and drug use. STI screens were performed on 269 patients with nine (3.3%) new HIV diagnoses, four (1.5%) early syphilis, and 28 (10.4%) rectal gonorrhoea infections. There were three (1.1%) new HCV diagnoses, and one (33.3%) was in an HIV negative patient.

Conclusions

Our results show increased risk behaviour for both HIV positive and HIV negative MSM. There are a high number of patients using party drugs, participating in group sex and not using condoms, leading to high rates of new STI diagnoses. With similar rates of risk we believe HCV testing and risk assessment should be considered in all MSM regardless of HIV status.
Transmission route and reasons for HIV testing among recently diagnosed HIV patients in HIV‐TR cohort, 2011–2012
Authors: Dokuzoguz Basak , Korten Volkan , Gökengin Deniz , Fincanci Muzaffer , Yildirmak Taner , Nuray Kes Uzun , Tasdelen Fisgin Nuriye , Inan Dilara , Eraksoy Haluk , Akalin Halis
Published: November 2014

Introduction

Routes of transmission and reasons for HIV testing are important epidemiologic data to analyze the epidemic and to tailor the response to AIDS. The aim of this study was to analyze reasons for testing and transmission ways of HIV among recently diagnosed HIV patients registered in the multicenter HIV‐TR cohort in Turkey.

Methods

Transmission ways and reasons for testing of all patients diagnosed in 2011 and 2012 were recorded on a web‐based data collection system and were analyzed retrospectively.

Results

The study included 693 patients (561 male, 132 female) from 24 sites. Reason for HIV testing was available in 640 patients (92%). The most common reason for HIV testing was diagnostic workout for other conditions or illness followed by patient‐initiated testing. The reasons for testing were listed in Table 1. The most common routes of HIV transmission were heterosexual intercourse (62.7%) and sex among men who have sex with men (MSM) (22.6%). At the time of HIV diagnosis, the mean CD4 lymphocyte cell count was 355/mm3 (3–1433/mm3). Primary HIV infection was determined in 42/693 (6%) patients and 9/693 (% 1, 2) cases were considered “probable primary HIV infection.” The majority of the cases presented to a clinic for follow‐up right after the diagnosis. On the other hand 32/616 (5.2%) patients delayed their presentation for more than 3 months. The longest delay was 11 months.

Conclusions

The results of the database suggest that targeted testing is lacking in the country. The shift toward homosexual transmission during the last 2 years emphasizes the need for targeted interventions. Patients present relatively late and HIV infection could only be diagnosed when immunosuppression related findings appeared. Patient‐initiated testing,an indicator of awareness, was very low suggesting a need to scale‐up awareness raising interventions.
Cost/efficacy analysis of preferred Spanish AIDS study group regimens and the dual therapy with LPV/r+3TC for initial ART in HIV infected adults
Authors: Gatell Josép M , Arribas José R , Lázaro Pablo , Blasco Antonio
Published: November 2014

Introduction

The National AIDS Plan and the Spanish AIDS study group (GESIDA) panel of experts propose “preferred regimens” of antiretroviral treatment (ART) as initial therapy in HIV‐infected patients for 2013 [1]. All these regimens are triple therapy regimens. The Gardel Study assessed the efficacy and safety of a dual therapy (DT) combination of lopinavir/ritonavir (LPV/r) 400/100 mg BID+ lamivudine (3TC) 150 mg BID [2]. The objective of this study is to evaluate the costs and efficiency of initiating treatment with the GESIDA “preferred regimens” and DT.

Materials and Methods

Economic assessment of costs and efficiency (cost/efficacy) through decision tree analysis models. Efficacy was defined as the probability of having viral load <50 copies/mL at week 48, in an intention‐to‐treat analysis. Cost of initiating treatment with an ART regime was defined as the costs of ART and its consequences (adverse effects, changes of ART regime and drug resistance tests) during the first 48 weeks. The payer perspective (Spanish National Health System) was applied considering only differential direct costs: ART (official prizes), management of adverse effects, resistance tests, and determination of HLA B*5701. The setting is Spain and the costs are those of 2013. A sensitivity deterministic analysis was conducted, building three scenarios for each regime: base, most favourable and most unfavourable cases.

Results

In the base case scenario, the cost of initiating treatment ranges from 5138 euros for DT, to 12,059 euros for tenofovir DF/emtricitabine (TDF/FTC)+raltegravir (RAL). The efficacy ranges between 0.66 for abacavir (ABC)/3TC+LPV/r and ABC/3TC+atazanavir (ATV)/r, and 0.88 for DT. Efficiency, in terms of cost/efficacy, varies between 5817 and 13,930 euros per responder at 48 weeks, for DT and TDF/FTC+RAL respectively. DT is the most efficient regimen in the most favourable (5503 euros per responder) and most unfavourable (6169 euros per responder) scenarios.

Conclusions

Considering the ART official Spanish prizes, the most efficient regimen was DT, followed by the triple therapy with non‐nucleoside containing regimens. The sensitivity analysis confirms the robustness of these findings.
Prices of second‐line antiretroviral treatment for middle‐income countries inside versus outside sub‐Saharan Africa
Authors: Simmons Bryony , Hill Andrew , Ford Nathan , Ruxrungtham Kiat , Ananworanich Jintanat
Published: November 2014

Introduction

Antiretrovirals are available at low prices in sub‐Saharan Africa, but these prices may not be consistently available for middle‐income countries in other regions with large HIV epidemics. Over 30% of HIV infected people live in countries outside sub‐Saharan Africa. Several key antiretrovirals are still on patent, with generic production restricted. We assessed price variations for key antiretroviral drugs inside versus outside sub‐Saharan Africa.

Methods

HIV drug prices used in national programmes (2010–2014) were extracted from the WHO Global Price Reporting Mechanism database for all reporting middle‐income countries as classified by the World Bank. Treatment costs (branded and generic) were compared for countries inside sub‐Saharan Africa versus those outside. Five key second‐line antiretrovirals were analysed: abacavir, atazanavir, darunavir, lopinavir/ritonavir, raltegravir.

Results

Prices of branded antiretrovirals were significantly higher outside sub‐Saharan Africa (p<0.001, adjusted for year of purchase) (see Table 1). For example, the median (interquartile range) price of darunavir from Janssen was $732 (IQR $732‐806) per person‐year in sub‐Saharan Africa versus $4689 (IQR $4075‐5717) in non‐African middle‐income countries, an increase of 541%. However, when supplied by generic companies, most antiretrovirals were similarly priced between countries in sub‐Saharan Africa and other regions.

Conclusions

Pharmaceutical companies are selling antiretrovirals to non‐African middle‐income countries at prices 74–541% higher than African countries with similar gross national incomes. However, generic companies are selling most of these drugs at similar prices across regions. Mechanisms to ensure fair pricing for patented antiretrovirals across both African and non‐African middle‐income countries need to be improved, to ensure sustainable treatment access.
Acceptability and confidence in antiretroviral generics of physicians and HIV‐infected patients in France
Authors: Allavena Clotilde , Jacomet Christine , Pereira Bruno , Morand‐Joubert Laurence , Bagheri Haleh , Cotte Laurent , Garaffo Rodolphe , Gerbaud Laurent , Dellamonica Pierre
Published: November 2014

Introduction

Switching brand name medications to generics is recommended in France in the interest of cost effectiveness but patients and physicians are sometimes not convinced that switching is appropriate. Some antiretroviral (ARV) generics (ZDV, 3TC, NVP) have been marketed in France since 2013.

Materials and Methods

A multicentric cross‐sectional survey was performed in September 2013 to evaluate the perception of generics overall and ARV generics in physicians and HIV‐infected patients and factors associated to their acceptability. Adult HIV outpatients were asked to complete a self‐questionnaire on their perception of generics. Physicians completed a questionnaire on the acceptability of generics and ARV generics. Socio‐demographic data, medical history and HIV history were collected.

Results

116 physicians in 33 clinics (68% in University Hospital) included 556 patients (France‐native 77%, active employment 59%, covered by social Insurance 100%, homosexual/bisexual contamination 47%, median HIV duration 13 years, hepatitis coinfection 16%, on ARV therapy 95%). Overall, patients accepted and had confidence in generics in 76% and 55% of the cases, respectively. Switching ARVs for generics was accepted by 44% of the patients but only by 17% if the pill burden was going to increase. 75% of the physicians would prescribe generics, but this decreased to only 26% if the combo had to be broken. The main reasons for non‐prescription of generics were previous brand name ARV‐induced side effects (35%), refusal of generics overall (37%), lack of understanding of generics (26%), risk of non‐observance of treatment (44%), anxiety (47%) and depressive symptoms (25%). In multivariate analysis, factors associated with the acceptability of ARV generics in patients were the use of generics overall (p<0.001) and in physicians, the absence of concern regarding the drug efficacy (p<0.001) and being aware that the patient would accept generics overall (p=0.03) and ARV generics (p=0.04). No factors related to sociodemographic conditions, HIV status or comorbidities had a constrictive influence on the use of ARV generics.

Conclusion

Acceptability of ARV generics in this French population is mostly dictated by the patient's and physician's knowledge and use of generics overall. Switching ARV brand name to a generic would be better accepted if the pill burden remained unchanged.
Results from a national treatment database – does it matter which ART combination is prescribed in the real world?
Authors: Scott Gordon , Wallace Lesley
Published: November 2014

Introduction

Clinical trials frequently show differences in viral load (VL) response between antiretroviral therapy (ART) regimes. Patterns of prescribing vary from country to country (Mocroft et al. Infection 2014 Jun 6 [epub ahead of print]), and are likely to vary between individual clinics. Scotland has a national database that records VL results and specific ART regimes for every patient under care, thus allowing different prescribing patterns between clinical centres to be monitored. Does this reveal any difference in achievement of undetectable VL?

Materials and Methods

We interrogated the database held by Health Protection Scotland (HPS) that contains a record of every VL result matched against prescribed ART. Results were censored at the end of December 2013 and are based on the latest attendance of patients who have been under monitoring for at least six months. For simplicity, we have broken the results into class of drug rather than individual drugs for example, nucleoside reverse transcriptase inhibitor (NRTI) rather than lamivudine, abacavir etc. The data were analyzed using univariate Poisson regression.

Results

The anonymized records of 3302 individual patients who attended in 11 separate regions were scrutinized. Sixty‐eight different combinations of antiretroviral regimes were identified. The prescribing patterns for the five most frequently prescribed regimes in the four largest clinics are shown in Table 1, along with the overall percentage of patients with undetectable VL. A higher proportion of patients in Scotland who are prescribed regimes of NRTI×2 or NRTI/NtRTI plus PI have detectable VL but this is not statistically significant. Although the percentage of patients with VL<50 varies between regions 1 and 4 versus regions 2 and 3, this is also not statistically significant.

Conclusions

Overall, a high proportion of Scottish patients on ART have undetectable VL. Patterns of ART prescribing in Scotland do vary by region but there are no significant differences in outcome with regard to undetectable VL. There is a non‐significant trend which may be accounted for by differing levels of PI prescribing.
Determinants of HIV‐1 drug resistance in treatment‐naïve patients and its clinical implications in an antiretroviral treatment program in Cameroon
Authors: Zoufaly Alexander , Jochum Johannes , Hammerl Raffaela , Nassimi Nilofar , Raymond Yurika , Burchard Gerd‐Dieter , Schmiedel Stefan , Drexler Jan‐Felix , Naomi Kay Campbell , Taka Nchang , Awasom Charles , Metzner Karin , Jan van Lunzen , Feldt Torsten
Published: November 2014

Introduction

Facing the rapid scale‐up of antiretroviral treatment (ART) programs in resource‐limited settings, monitoring of treatment outcome is essential in order to timely detect and tackle drawbacks [1].

Methods

In a prospective cohort study, 300 consecutive patients starting first‐line ART were enrolled between 2009 and2010 in a large HIV treatment centre in rural Cameroon. Patients were followed up for 12 months. Virologic failure was defined as a VL >1000 cop/mL at month 12. Besides CD4 and viral load (VL) analysis, HIV‐1 drug resistance testing was performed in patients with VL>1000 copies (c)/mL plasma. In those patients and controls, minority HIV‐1 drug resistance mutations at baseline, and plasma drug levels were analyzed in order to identify the risk factors for virologic failure.

Results

Most enrolled patients (71%) were female. At baseline median CD4 cell count was 162/µL (IQR 59‐259), median log10 VL was 5.4 (IQR 5.0–5.8) c/mL, and one‐third of patients had World Health Organisation (WHO) stage 3 or 4; 30 patients died during follow‐up. Among all patients who completed follow‐up 38/238 had virologic failure. These patients were younger, had lower CD4 cell counts and more often had WHO stage 3 or 4 at baseline compared to patients with VL<1000c/mL. Sixty‐three percent of failing patients (24/38) had at least one mutation associated with high‐level drug resistance. The M184V mutation was the most frequently detected nucleoside reverse transcriptase inhibitor (NRTI) mutation (n=18) followed by TAMs (n=5) and multi‐NRTI resistance mutations (n=4). The most commonly observed non‐nucleoside reverse‐transcriptase inhibitor (NNRTI) resistance mutations were K103N (n=10), Y181C (n=7), and G190A (n=6). Drug resistance mutations at baseline were detected in 12/65 (18%) patients, in 6 patients with and 6 patients without virological failure (p=0.77). Subtherapeutic NNRTI levels (OR 6.67, 95% CI 1.98–22.43, p<0.002) and poorer adherence (OR 1.54, 95% CI 1.00–2.39, p=0.05) were each associated with higher risk of virologic failure in the matched pair analysis. Unavailability of ART at the treatment centre was the single most common cause (37%) for incomplete adherence in these patients.

Conclusions

Virologic failure after one year of first‐line ART in rural Cameroon was not associated with transmitted drug resistance, but with reduced drug plasma levels and incomplete adherence. Strategies to assure adherence and uninterrupted drug supply are important factors for therapy success.
AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be
Authors: Gisler Valentin , Kraus David , Nemeth Johannes , Than Lecompte Marthe , Merz Laurent , Stoeckle Marcel , Schmid Patrick , Bernasconi Enos , Weber Rainer , Cavassini Matthias , Calmy Alexandra , Elzi Luigia , Furrer Hansjakob
Published: November 2014

Introduction

According to reports from observational databases, classic AIDS‐defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART.

Materials and Methods

In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non‐immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in‐depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune‐compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation.

Results

More than 13,000 participants were followed in SHCS in the period of interest. Twenty‐four (48%) of the chart‐reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune‐compromising conditions such as immunosuppressive drugs in 14 (34%).

Conclusions

In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno‐compromising conditions are more likely explanations in one‐third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.