‏إظهار الرسائل ذات التسميات observational. إظهار كافة الرسائل
‏إظهار الرسائل ذات التسميات observational. إظهار كافة الرسائل

الاثنين، 3 سبتمبر 2012

Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study)

Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study) | BMJ

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Research Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study) BMJ 2012; 345 doi: 10.1136/bmj.e5339 (Published 29 August 2012) Cite this as: BMJ 2012;345:e5339 Degenerative joint disease Musculoskeletal syndromes Osteoarthritis Pain (neurology) More topics

Immunology (including allergy) Clinical diagnostic tests Radiology Radiology (diagnostics) Calcium and bone Health education Health promotion Obesity (nutrition) Obesity (public health) Fewer topics

Article Related content Article metrics Ali Guermazi, professor of radiology1, Jingbo Niu, research assistant professor of medicine2, Daichi Hayashi, research assistant professor of radiology1, Frank W Roemer, associate professor of radiology13, Martin Englund, associate professor, epidemiologist24, Tuhina Neogi, associate professor of medicine and epidemiology2, Piran Aliabadi, professor of radiology5, Christine E McLennan, project manager6, David T Felson, professor of medicine and epidemiology2
1Department of Radiology, Boston University School of Medicine, FGH Building, 820 Harrison Avenue, Boston, MA 02118, USA
2Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston
3Klinikum Augsburg, Department of Radiology, Augsburg, Germany
4Lund University, Clinical Sciences Lund, Department of Orthopaedics, Lund, Sweden
5Brigham and Women’s Hospital, Harvard Medical School, Department of Radiology, Boston, MA 02115
6OptumInsight Life Sciences, Waltham, MA 02451Correspondence to: A Guermazi guermazi{at}bu.eduAccepted 23 July 2012AbstractObjective To examine use of magnetic resonance imaging (MRI) of knees with no radiographic evidence of osteoarthritis to determine the prevalence of structural lesions associated with osteoarthritis and their relation to age, sex, and obesity.

Design Population based observational study.

Setting Community cohort in Framingham, MA, United States (Framingham osteoarthritis study).

Participants 710 people aged >50 who had no radiographic evidence of knee osteoarthritis (Kellgren-Lawrence grade 0) and who underwent MRI of the knee.

Main outcome measures Prevalence of MRI findings that are suggestive of knee osteoarthritis (osteophytes, cartilage damage, bone marrow lesions, subchondral cysts, meniscal lesions, synovitis, attrition, and ligamentous lesions) in all participants and after stratification by age, sex, body mass index (BMI), and the presence or absence of knee pain. Pain was assessed by three different questions and also by WOMAC questionnaire.

Results Of the 710 participants, 393 (55%) were women, 660 (93%) were white, and 206 (29%) had knee pain in the past month. The mean age was 62.3 years and mean BMI was 27.9. Prevalence of “any abnormality” was 89% (631/710) overall. Osteophytes were the most common abnormality among all participants (74%, 524/710), followed by cartilage damage (69%, 492/710) and bone marrow lesions (52%, 371/710). The higher the age, the higher the prevalence of all types of abnormalities detectable by MRI. There were no significant differences in the prevalence of any of the features between BMI groups. The prevalence of at least one type of pathology (“any abnormality”) was high in both painful (90-97%, depending on pain definition) and painless (86-88%) knees.

Conclusions MRI shows lesions in the tibiofemoral joint in most middle aged and elderly people in whom knee radiographs do not show any features of osteoarthritis, regardless of pain.

IntroductionAgeing of the population and increasing obesity contribute to morbidity worldwide. Osteoarthritis is the most prevalent medically treated arthritic condition worldwide (for example, 3532 per 100?000 people in the United States).1 2 Diagnosis of osteoarthritis is made on the basis of clinical examination or radiography. Population based longitudinal studies in the US3 and the United Kingdom4 showed the lifetime risk of knee osteoarthritis increases with age,3 with the risk highest in obese people.3 4 Other prevalence surveys showed that radiographic osteoarthritis of the knee is common in middle aged and older adults.5 6

Although many publications have reported structural changes in people with radiographic knee osteoarthritis, few data are available regarding what structural changes are present in knees without any radiographic features of osteoarthritis. About half of people with knee pain have no radiographic osteoarthritis. In clinical practice, it is unclear how to investigate and manage such people and whether additional imaging with magnetic resonance imaging would be of clinical value. Such data can be collected only in population based studies as people with normal knees are not usually enrolled into clinical studies or undergo further imaging evaluation. Radiography can show osteophytes, bony outgrowths at the joint margin, and narrowing of the joint space, but it cannot visualise soft tissue pathology.7 In contrast, MRI can visualise various tissues that are clinically relevant and have an important role in regard to structural progression not seen on radiography. MRI can also show incidental findings in otherwise asymptomatic people.8 9 In the knee, MRI visualises most components of the joint, including articular cartilage, menisci, intra-articular ligaments, synovium, bone marrow, subchondral cysts, and other periarticular and intra-articular lesions that are not detectable by radiography.10

We used MRI to evaluate the presence of structural changes in knees that were free from radiographic tibiofemoral osteoarthritis. We focused on the tibiofemoral joint, which includes numerous bony and soft tissue structures that can be evaluated by MRI. We evaluated the prevalence of cartilage damage, meniscal lesions, osteophytes, subchondral cysts, bone marrow lesions, ligamentous lesions, attrition, and synovitis on MRI in participants of the Framingham Osteoarthritis Study who had radiographically normal tibiofemoral knee joints. We also assessed whether the prevalence of these features differed according to age, sex, body mass index (BMI), or knee pain.

MethodsStudy design and participantsThe Framingham Community cohort was recruited from the Framingham, MA, census tract data for the year 2000 and random digit telephone dialling. All participants were examined between 2002 and 2005. This study cohort is distinct from the Framingham Heart Study and the Framingham Offspring Study cohorts. Participants were not selected on the basis of having knee or other joint problems, and potential participants were not told that knees were a focus of the study.

Eligible participants were aged at least 50 and ambulatory (the use of assistive devices such as canes and walker was permitted), with no plans to move out of the area for at least five years to accommodate the possibility of longitudinal follow-up. We excluded those with a history of bilateral total knee replacement, rheumatoid arthritis, dementia, or terminal cancer and those who had contraindications to MRI. Of 2582 people aged 50 or older and living in Framingham who were contacted by random digit dialling, 1830 expressed interest in participating in the study.8 Of those, 39 were lost to contact, 194 were ineligible for the study, and 558 declined to participate. Consequently, 1039 were examined, 993 underwent MRI, and 992 had readable scans (one knee per participant, right knee preferred; left knee if right knee not available (fig 1?).

View larger version:In a new windowDownload as PowerPoint SlideFig 1 Selection process of knees included in present study

Knee radiography and gradingParticipants underwent weight bearing posteroanterior knee radiography with the fixed-flexion protocol.11 One musculoskeletal radiologist, who was blinded to the MRI findings and clinical data, graded radiographs using the Kellgren-Lawrence grading system (intraobserver ? 0.83).12 13 Because we wanted to focus on “normal” tibiofemoral knee joints (Kellgren-Lawrence grade 0), we excluded 253 participants with radiographic tibiofemoral osteoarthritis (Kellgren-Lawrence grade 2 or above), doubtful or equivocal findings of radiographic evidence of tibiofemoral osteoarthritis (Kellgren-Lawrence grade 1), or missing radiographs or radiographic readings. Finally, we excluded 30 participants because of unreadable or poor quality MRIs. This resulted in 710 radiographically “normal” tibiofemoral knee joints being included in the final sample for analysis (fig 1?).

MRI grading of osteoarthritis featuresMRI was done with a 1.5 Tesla scanner (Siemens Medical Systems, Erlangen, Germany) with a phased array knee coil. Images from four pulse sequences were used in the assessment of osteoarthritis features: axial, sagittal and coronal fat saturated, proton density weighted, turbo spin echo images (repetition time 3610 msec; echo time 40 msec; slice thickness 3.5 mm; interslice gap 0 mm; echo train length 7; field of view 140 mm × 140mm; matrix 256 × 256) and sagittal T1 weighted spin echo images without fat saturation (repetition time 475 msec; echo time 24 msec; slice thickness 3.5 mm; interslice gap 0 mm; field of view 140 mm×140 mm; matrix 256×256).

MRI scans were read by two trained and experienced musculoskeletal radiologists (who did not read the radiographs) using a standardised and validated method called the whole organ magnetic resonance imaging score (WORMS).14 They recorded the presence or absence of the specific features (described below) related to osteoarthritis that were included in our assessment of the tibiofemoral joint (that is, tibial plateaus and the central weight bearing and posterior portions of femoral condyles). In the WORMS system, the tibiofemoral joint is subdivided into 10 different subregions for scoring of each feature. Readings from all subregions were amalgamated within the knee.14 Agreement between observers (? statistic) for the detection of the MRI features was as follows: cartilage damage 0.89; meniscal lesions 0.71; osteophytes 0.73; ligamentous lesions 0.49; bone marrow lesions 0.85; subchondral cysts 0.57; and synovitis 0.63. The relatively low value of ? for ligamentous lesions was because few knees had ligamentous lesions in the reliability sample.

Cartilage damage was considered present if there was a small focal loss less than 1 cm in greatest width or areas of diffuse partial or full thickness loss (WORMS grade =2). In this study we did not consider intrachondral signal alterations (WORMS grade 1), which are thought to occur before cartilage damage develops14 but are of unknown clinical importance, to represent cartilage damage.

Meniscal lesions (WORMS grade =1) included displaced or non-displaced meniscal tears or evidence of previous surgery (including repair and partial or complete resection) and complete maceration or destruction (that is, loss of normal contour and signal homogeneity within the meniscus) within the anterior and posterior horns and the body of the medial and lateral menisci.14

Osteophytes were considered present if there were bony projections that form along different margins of the tibiofemoral joint of the knee (WORMS grade =2). Tiny bony spurs that were equivocal on visual evaluation (that is, “lipping,” WORMS grade =1) were not considered as osteophytes.

Ligamentous abnormalities were defined as the presence of a completely torn anterior or posterior cruciate ligament, or a torn or thickened medial or lateral collateral ligament (WORMS grade =1).

Bone marrow lesions—Subchondral bone marrow lesions, also known as “bone marrow edema-like lesions,”15 were considered present if there are non-cystic subchondral areas of ill defined high signal on proton density weighted MR images with fat signal suppression (WORMS grade =1).

Subchondral cysts were identified as areas of markedly increased signal intensity in the subarticular bone with sharply defined rounded margins and no evidence of internal marrow tissue or trabecular bone on the fat saturated proton density weighted images (WORMS grade =1).

Synovitis was considered present if the synovial cavity was distended and filled with fluid (high signal intensity on fat saturated proton density weighted images), representing synovial thickening and joint effusion (WORMS grade =1).14

Attrition—Flattening or depression of the articular surfaces of the tibia or femur was termed bone attrition, and any degree of deviation from the normal bony contour was considered abnormal (WORMS grade =1).

Additional analysis with a more stringent definition of “abnormality”Currently there is no concrete definition of what is “abnormal” in terms of MRI findings in the knee, and the use of different cut off points for the definition of “abnormality” might produce different results. We also examined a more stringent definition of lesions detected by MRI, which included cartilage damage and osteophytes=WORMS grade =3; all other lesions=grade =2.

Assessment of weight, height, and pain We measured the participants’ weight when they were not wearing shoes with the use of a balance beam scale and measured height with a stadiometer. At the clinic visit all participants were asked about knee symptoms with the following question: “In the past month, have you had any pain, aching, or stiffness in your knee?” (for this study, we focused on pain in the knee with MRI reading). Additionally, we assessed knee pain in three more ways. Participants responded to the questions, “Did you have knee pain lasting at least a month in the past year?” and “Do you have knee pain on most days?” A positive response to these questions was considered to indicate the presence of knee pain. Each participant was also asked to fill out the Western Ontario McMaster University arthritis index (WOMAC) questionnaire, and any score =1 in the pain subscale in the knee was considered to indicate the presence of knee pain. For WOMAC pain, we restricted our analysis to participants who had Kellgren-Lawrence grade 0 knees bilaterally as the WOMAC questionnaire was person based and not knee based.

Statistical analysisWe calculated the prevalence of the aforementioned osteoarthritis features on MRI and stratified the data according to sex, age group (sixth decade, seventh decade, and older), BMI (<25, =25-<30, =30), and the presence of pain. We used ?2 tests to assess the presence of significant differences between men and women, and among different age and BMI groups. For cartilage and bone marrow lesions, results were stratified according to the medial and lateral tibiofemoral compartments of the knee. All statistical analyses were performed with SAS for Windows, version 9.1. Results were considered to be significant when a two tailed P<0.05.

ResultsCharacteristics of study sampleOf the 710 participants, 393 (55%) were women, 660 (93%) were white, and 206 (29%) had painful knees. The mean age was 62.3 (range 51-89), and the mean BMI was 27.9 (range 16.6-50.6) (table 1?).

View this table:View PopupView InlineTable 1 Characteristics of participants without knee abnormalities. Figures are numbers (percentage) unless stated otherwise

Prevalence of bony and soft tissue abnormalities on MRI with standard definitionOverall, 631 (89%) knees had at least one type of abnormality (fig 2?, table 2?). The three most common findings were osteophytes, cartilage damage, and bone marrow lesions. In the location specific analysis, cartilage damage was more prevalent in the medial tibiofemoral compartment (33% (95% confidence interval 30% to 37%), 235/710) than in the lateral tibiofemoral compartment (20% (17% to 23%), 141/710). Likewise, there were more bone marrow lesions in the medial (19% (16% to 22%), 133/710) than in the lateral tibiofemoral compartment (12% (10% to 16%), 87/710).

View larger version:In a new windowDownload as PowerPoint SlideFig 2 Knee with multiple abnormalities on MRI indicating early stage osteoarthritis despite lack of radiographic osteoarthritis. A: coronal fat suppressed proton density weighted image shows several features of early OA detectable only by MRI. White arrowhead shows focal full thickness cartilage defect at central weight bearing part of medial femur. In addition there is adjacent subchondral bone marrow lesion presenting as area of ill defined hyperintensity (arrows). Black arrowheads show meniscal extrusion at medial joint line causing bulging of neighbouring medial collateral ligament (no arrow). B: sagittal proton density weighted image shows isolated degenerative horizontal oblique tear of posterior horn of medial meniscus extending to undersurface of meniscus adjacent to posterior tibial surface (arrows). No associated cartilage damage or subchondral bony alterations are seen

View this table:View PopupView InlineTable 2 Prevalence of MRI features (standard definition*) stratified by sex, pain status, and BMI. Figures are numbers (percentage) of participants

Table 2 summarises the prevalence of each MRI feature overall and in men and women?. The prevalence of meniscal lesions was significantly higher in men than in women (110/317 (35%) v 57/393 (15%); P<0.001). No other features were significantly different between men and women. There were no significant differences in the prevalence of any of the features between BMI groups (table 2). The prevalence of all features was within about 7% among all BMI groups.

Older age groups had more abnormalities of all types. Of the participants in their sixth decade, 86% (271/316) had features of osteoarthritis. The rate increased to 91% (227/249) in the seventh decade and 92% (133/145) in the oldest age group. Specific types of abnormalities (cartilage damage, meniscal lesions, osteophytes, subchondral cysts) also increased with each decade (table 3? and fig 3?). The prevalence of ligamentous lesions, bone marrow lesions, attrition, and synovial thickening and joint effusion was also higher in older age groups, but the differences between groups were not significant.

View this table:View PopupView InlineTable 3 Prevalence of MRI features (standard definition*) stratified by age group. Figures are numbers (percentage) of participants

View larger version:In a new windowDownload as PowerPoint SlideFig 3 Prevalence of osteoarthritis features on MRI in knees without radiographic osteoarthritis stratified by age group with standard and more stringent definitions of MRI abnormalities

The prevalence of attrition (38% v 30%; P=0.04), bone marrow lesions (59% v 50%; P=0.03), and subchondral cysts (31% v 23%; P=0.04) was higher in participants with painful knees than those without pain (table 2). The prevalences for the other features were within about 4% of one another among painful and painless knees with no significant differences (table 2). Indeed, the prevalence of at least one type of MRI detected pathology (“any abnormality”) was high in both painful (91%) and painless (88%) knees (table 2?). Regardless of the definition of pain used, MRI detected abnormalities were highly prevalent in people with (90-97%) and without (86-88%) knee pain. While the prevalence of MRI abnormalities was not significantly different in those with versus those without knee pain for most definitions of pain we tested, the prevalence of “any MRI abnormality” was higher in those with WOMAC pain compared with those without pain (P=0.002). Even so, the prevalence of any MRI abnormality was as high as 86% in those without WOMAC pain.

Prevalence of bony and soft tissue abnormalities on MRI with more stringent definitionWhen we used the more stringent definition of MRI abnormality, overall the prevalence of MRI detected lesions dropped as expected (table 4?), to 14% for osteophytes, 44% for cartilage damage, 16% for bone marrow lesions, 4% for synovitis, 10% for attrition, 5% for subchondral cysts, 8% for meniscal lesions, and 2% for ligamentous lesions. The prevalence of any abnormality, however, remained high (53%, 373/710). Except for bone attrition, painful knees did not differ from those without pain in terms of the prevalence of specific features (table 4?). Regardless of the definition of pain used, any abnormality was present in 57-70% of participants with pain and about half of those without pain (table 5?). There were significant differences between groups with and without pain in three out of four definitions of pain, and the largest difference was seen with WOMAC pain (15%, P<0.001). Prevalence of “any abnormality” in those without WOMAC pain, however, was still high (48%).

View this table:View PopupView InlineTable 4 Prevalence of MRI features (more stringent definition*) stratified by sex, pain status, and BMI. Figures are numbers (percentage) of participants

View this table:View PopupView InlineTable 5 Prevalence of “any abnormality” on MRI stratified by pain status with standard and more stringent definitions of pain. Figures are numbers (percentage) of participants

DiscussionWe found that MRI detected features of osteoarthritis are highly prevalent in the tibiofemoral joint of knees that did not have any radiographic features of osteoarthritis in participants both with and without knee pain. Nearly 90% of our participants had at least one feature of osteoarthritis on MRI. Osteophytes were the most common, followed by cartilage damage and bone marrow lesions. In general, the older the age group, the higher the prevalence of features of osteoarthritis, although differences among age groups were not significant for synovitis and effusion and of borderline significance for ligamentous lesions and bone marrow lesions. Only meniscal lesions were more prevalent in men than women. No significant differences were observed for any type of lesions by BMI.

Strengths and limitationsThis population based study documented the high prevalence of MRI features suggestive of knee osteoarthritis in people without radiographic osteoarthritis. We included only knees that were definitely lacking any radiographic features that could indicate the presence of osteoarthritic changes (Kellgren-Lawrence grade 0) to ensure our analysis is specific. Although Kellgren-Lawrence grade 1 knees also do not qualify for having radiographic osteoarthritis, a “doubtful” bony abnormality is present and one could argue such equivocal findings are difficult to interpret.

Limitations Our sample was primarily (although not exclusively) white, reflecting the population of Framingham, MA. The number of people from other racial or ethnic groups was too small for comparisons. Our prevalence estimates cannot be generalised to adults younger than 50. In particular, meniscal lesions in young active otherwise healthy adults are more likely to be caused by trauma than the degenerative process seen in middle aged and older people. We had no arthroscopic correlation of our MRI findings. Ideally, intra-articular pathology (that is, cartilage, meniscus, and ligaments) should be confirmed by direct visualisation during arthroscopy. Arthroscopy, however, is neither feasible nor ethical in large scale population based studies. Furthermore, arthroscopy cannot visualise some of the MRI findings that are indicative of the osteoarthritis disease process such as subchondral bone marrow lesions. Nearly all the knees in our sample were right knees (with only five left knees). A comparison of 99 people with both right and left knee MRIs in this sample, however, showed no difference in findings, and which knee is studied is therefore unlikely to affect our overall outcome. We did not include the evaluation of radiographic patellofemoral joint pathology in this study because we used the posteroanterior radiograph to classify the tibiofemoral joint of the knee using Kellgren-Lawrence grading. We dealt with this fact by including only subregions of the knee that correspond to the tibiofemoral joint for MRI analysis.

Because we focused on knees with clearly normal radiographic appearance (Kellgren-Lawrence grade 0), we excluded Kellgren-Lawrence grade 1 knees. One might argue that such knees are also without radiographic osteoarthritis and warrant inclusion in our analysis. Inclusion of the 39 Kellgren-Lawrence grade 1 knees in our sample (total 749 knees) did not alter the demographic characteristics of the participants or analytical results for all aspects of the study. There are many ways to define pain, and it is not possible to include all different pain assessment tools available to date in a single study. We selected the WOMAC pain subscale because it has been validated and is widely used.16 17

Our results raise additional questions. More detailed analysis evaluating the factors that could contribute to the differences seen in men and women and the osteoarthritis features in the different age groups would be of interest. Also, comparison of the prevalence of these findings in those with and without radiographic osteoarthritis would tackle the question of whether osteoarthritis is an inevitable consequence of ageing.

Comparison with previous studiesOf our findings, the most notable is that 74% of the knees had osteophytes. As a bony abnormality should be clearly visible on radiograph, we did not expect the prevalence to be this high. Presumably, because the MRI assessment used three imaging planes, it could detect osteophytes that were hidden by the overlapping femur or tibia on posteroanterior view radiographs. This is a substantial problem as the presence of definite osteophytes defines the diagnosis of radiographic osteoarthritis.12 Thus far, epidemiological or clinical studies of knee osteoarthritis depend largely on the radiographic definition of osteoarthritis.18 19 As radiography fails to detect such a large proportion of osteophytes, there could be misclassification of a large number of potentially eligible people in knee osteoarthritis studies and underestimation of the true prevalence of this condition.20

Although cartilage itself is aneural and is unlikely to be a direct cause of knee pain, cartilage damage is associated with change in bone marrow lesions,21 high BMI, meniscal damage, and synovitis or effusion.22 Cartilage thickness has traditionally been assessed by its surrogate marker—the radiographic width of the joint space of the tibiofemoral joint. Narrowing of the joint space, however, can result not only from cartilage damage but also from meniscal lesions.23 It has been shown that radiography is less sensitive than MRI for detection of cartilage loss.7 Thus, it is not surprising to find a high prevalence of cartilage damage on MRI in the knees of middle aged and older people without radiographic joint space narrowing.

The presence and extent of bone marrow lesions and synovial thickening/effusion can be appreciated only on MRI. These lesions have been associated with pain in knees with osteoarthritis.24 25 Furthermore, in people at high risk of developing osteoarthritis, bone marrow lesions in asymptomatic knees with no radiographic osteoarthritis at baseline predict development of pain 15 months later.26 We also found an association of bone marrow lesions with knee pain among people without radiographic osteoarthritis.

A high prevalence of incidental meniscal findings on MRI in participants of the Framingham Osteoarthritis Study has been reported previously.8 One or more meniscal tears was present in 32% (41/127) of knees with symptoms, 23% (146/548) of knees without symptoms, and 24% (187/775) overall when there was no or equivocal radiographic evidence of osteoarthritis. Although the results were similar to the present study, they are not identical because Englund and colleagues included knees with Kellgren-Lawrence grade 0 and 1,8 whereas we focused on Kellgren-Lawrence grade 0.

We saw fewer incidental ligamentous lesions than any other feature. This could be because the semiquantitative scoring system we used only scores a complete tear as a lesion, and partial tears are given a score of zero. Imaging diagnosis of partial ligamentous tears on MRI can be difficult. The role of intra-articular and periarticular ligaments of the knee in predicting structural progression of knee osteoarthritis remains unclear. Disruption of the integrity of these ligaments, however, will probably cause alterations in knee kinematics.

A recent systematic review reported that bone marrow lesions and effusion/synovitis were associated with knee pain.27 In our study, however, these lesions were not significantly more prevalent in participants who had knee pain than in those without, with both definitions of MRI abnormality. This discrepancy is probably because the systematic review included only studies involving mostly people with radiographic knee osteoarthritis. Thus, the conclusion of the systematic review is not applicable to the present study.

Clinical implicationsOur findings indicate that the prevalence of MRI detected osteoarthritis features increases with age in the absence of radiographic features of osteoarthritis. We have shown that MRI is more sensitive than radiographs to changes in bone and soft tissue that are considered features of osteoarthritis,28 29 Our data showed that the prevalence of these MRI detected features is high irrespective of the knee pain status. When we compared the prevalence of MRI abnormalities in knees in people with and without pain, there were two trends. Firstly, and most importantly, the prevalence of MRI findings was extremely high in those without pain, suggesting that using MRI as a diagnostic test for people with normal knee radiographs in this age group would have poor specificity. Secondly, the prevalence of findings was modestly higher in those with pain than in those without, with the difference sometimes reaching significance. These differences, however, were not particularly informative—for example, the highest prevalence of MRI abnormalities was actually in those with mild pain rather than moderate or severe pain.

Thus, MRI features suggestive of osteoarthritis in people without radiographic osteoarthritis are commonly seen in those with or without knee pain, implying that MRI alone is not diagnostically useful to discriminate between people with and without pain in the context of knee osteoarthritis. MRI might still play an important diagnostic role, especially in younger people, in whom other reasons for knee pain should be considered such as inflammatory arthritides, insufficiency fractures, or spontaneous osteonecrosis. Nonetheless, in all likelihood, MRI features of osteoarthritis will be found regardless of the source of the pain. Our study also highlights the limitations of conventional radiography to detect a large number of abnormalities related to osteoarthritis in the knee.20

As high BMI is a known risk factor for both incident knee osteoarthritis and for progression of knee osteoarthritis30 31 we expected to see higher prevalence of MRI features in obese people compared with non-obese people. We did not find high BMI to be associated with higher prevalence of MRI features overall compared with low BMI, but rather that these MRI abnormalities were equally highly prevalent in all BMI groups. We speculate that BMI is important for progression of later stages of osteoarthritis, but potentially age is a much more relevant trigger of early stages of osteoarthritis.

Although there is thought to be only a modest correlation between clinical symptoms and radiographic tibiofemoral osteoarthritis,32 recent work has highlighted an association between structural osteoarthritis pathology and knee pain.33 34 It is important for the clinical community to recognise that findings that would be interpreted as abnormal and suggestive of disease are in fact present in most knees without any pain, even when different definitions of pain are used. That means that the clinical significance of these MRI findings is questionable. The same message has been reported for radiographic findings in patients with low back pain (similar highly prevalent abnormalities were seen in those without low back pain), and this led to discouraging radiographic evaluations in those with low back pain.35

ConclusionsChanges indicative of osteoarthritis are commonly present in the knees of most people aged 50 and over who have no radiographic evidence of tibiofemoral osteoarthritis. Osteophytes, cartilage damage, and bone marrow lesions are especially common among middle aged and older people. These features are common in knees with pain and in those that are painless and can potentially represent pre-radiographic or early stage osteoarthritis. A longitudinal study is needed to determine what proportion of people without radiographic osteoarthritis but with MRI abnormalities subsequently develop radiographic osteoarthritis.

What is already known on this topicMRI can detect features suggestive of knee osteoarthritis that cannot be visualised on conventional radiography, which is insensitive to many findings

In roughly half of people with knee pain, radiography shows no abnormalities

What this study addsChanges indicative of osteoarthritis are commonly present in the knees of most people aged 50 and over who have no radiographic evidence of tibiofemoral osteoarthritis

MRI detected findings of osteoarthritis are common in people with and without knee pain, suggesting that the clinical significance of MRI findings in such knees is not clear

NotesCite this as: BMJ 2012;345:e5339

FootnotesContributors: AG, JN, DH, and DTF conceived and designed the study. AG, JN, FWR, PA, CEM, and DTF collected the data. AG, DH, FWR, ME, TN, and DTF reviewed the literature. AG, JN, DH, FWR, ME, TN, and DTF directed the analyses, which were carried out by JN. All authors participated in the discussion and interpretation of the results. AG and DH organised the writing and wrote the initial drafts. All authors critically revised the manuscript for intellectual content and approved the final versions. AG and DTF are guarantors.

Funding: This study was funded by the National Institutes of Health (AG18393 and AR47785) and the Arthritis Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The researchers work independently of their funders.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: AG is the president of Boston Imaging Core Lab (BICL), LLC, and a consultant to Merck Serono, Stryker, Genzyme, AstraZeneca, and Novartis; FWR a vice president and shareholder of BICL and is a consultant to Merck Serono and National Institute of Health; ME is funded by the Swedish Research Council, the Greta and Johan Kock Foundation, King Gustaf V 80-year Birthday Foundation, and the Faculty of Medicine, Lund University, Sweden; TN is supported by NIAMS AR055127 and the Arthritis Foundation Arthritis Investigator Award.

Ethical approval: This study was approved by the institutional review board of Boston University Medical Centre (protocol number H-22674), and written informed consent was obtained from all participants.

Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

References?Sacks JJ, Luo YH, Helmick CG. Prevalence of specific types of arthritis and other rheumatic conditions in the ambulatory health care system in the United States, 2001-2005. Arthritis Care Res (Hoboken)2010;62:460-4.OpenUrlCrossRefMedlineWeb of Science?Bedson J, Jordan K, Croft P. The prevalence and history of knee osteoarthritis in general practice: a case-control study. Fam Pract2005;22:103-8.OpenUrlFREE Full Text?Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum2008;59:1207-13.OpenUrlCrossRefMedlineWeb of Science?Wills AK, Black S, Cooper R, Coppack RJ, Hardy R, Martin KR, et al. Life course body mass index and risk of knee osteoarthritis at the age of 53 years: evidence from the 1946 British birth cohort study. Ann Rheum Dis2012;71:655-60.OpenUrlFREE Full Text?Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum1998;41:1343-55.OpenUrlCrossRefMedlineWeb of Science?Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum2008;58:26-35.OpenUrlCrossRefMedlineWeb of Science?Amin S, LaValley MP, Guermazi A, Grigoryan M, Hunter DJ, Clancy M, et al. The relationship between cartilage loss on magnetic resonance imaging and radiographic progression in men and women with knee osteoarthritis. Arthritis Rheum2005;52:3152-9.OpenUrlCrossRefMedlineWeb of Science?Englund M, Guermazi A, Gale D, Hunter DJ, Aliabadi P, Clancy M, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med2008;359:1108-15.OpenUrlCrossRefMedline?Vernooij MW, Ikram MA, Tanghe HL, Vincent AJ, Hofman A, Krestin GP, et al. Incidental findings on brain MRI in the general population. N Engl J Med2007;357:1821-8.OpenUrlCrossRefMedlineWeb of Science?Guermazi A, Roemer FW, Hayashi D. Imaging of osteoarthritis: update from a radiological perspective. Curr Opin Rheumatol2011;23:484-91.OpenUrlCrossRefMedline?Kothari M, Guermazi A, von Ingersleben G, Miaux Y, Sieffert M, Block JE, et al. Fixed-flexion radiography of the knee provides reproducible joint space width measurements in osteoarthritis. Eur Radiol2004;14:1568-73.OpenUrlMedlineWeb of Science?Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis1957;16:494-502.OpenUrlFREE Full Text?Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum1987;30:914-8.OpenUrlMedlineWeb of Science?Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. Whole-organ magnetic resonance imaging score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage2004;12:177-90.OpenUrlCrossRefMedlineWeb of Science?Roemer FW, Frobell R, Hunter DJ, Crema MD, Fischer W, Bohndorf K, et al. MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthritis Cartilage2009;17:1115-31.OpenUrlCrossRefMedlineWeb of Science?Theiler R, Sangha O, Schaeren S, Michel BA, Tyndall A, Dick W, et al. Superior responsiveness of the pain and function sections of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) as compared to the Lequesne-Algofunctional Index in patients with osteoarthritis of the lower extremities. Osteoarthritis Cartilage1999;7:515-9.OpenUrlCrossRefMedlineWeb of Science?Avasthi S, Sanghi D, Singh A, Kumar A, Kumar S, Misra A, et al. Significance of clinical parameters and role of clinical scoring systems in predicting severity of primary osteoarthritis knee. Int J Orthoped Surg2009;13:1.OpenUrl?Felson DT, Gale DR, Elon Gale M, Niu J, Hunter DJ, Goggins J, et al. Osteophytes and progression of knee osteoarthritis. Rheumatology (Oxford)2005;44:100-4.OpenUrlFREE Full Text?Guermazi A, Hunter DJ, Li L, Benichou O, Eckstein F, Kwoh CK, et al. Different thresholds for detecting osteophytes and joint space narrowing exist between the site investigators and the centralized reader in a multicenter knee osteoarthritis study-data from the Osteoarthritis Initiative. Skeletal Radiol2012;41:179-86.OpenUrlCrossRefMedlineWeb of Science?Sanghi D, Avasthi S, Mishra A, Singh A, Agarwal S, Srivastava RN. Is radiology a determinant of pain, stiffness, and functional disability in knee osteoarthritis? A cross-sectional study. J Orthop Sci2011;16:719-25.OpenUrlCrossRefMedline?Roemer FW, Guermazi A, Javaid MK, Lynch JA, Niu J, Zhang Y, et al. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann Rheum Dis2009;68:1461-5.OpenUrlFREE Full Text?Roemer FW, Zhang Y, Niu J, Lynch JA, Crema MD, Marra MD, et al. Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study. Radiology2009;252:772-80.OpenUrlFREE Full Text?Hunter DJ, Zhang YQ, Tu X, Lavalley M, Niu JB, Amin S, et al. Change in joint space width: hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheum2006;54:2488-95.OpenUrlCrossRefMedlineWeb of Science?Felson DT, Chaisson CE, Hill CL, Totterman SM, Gale ME, al. SKe. The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med2001;134:541-9.OpenUrlMedlineWeb of Science?Hill CL, Gale DG, Chaisson CE, Skinner K, Kazis L, Gale ME, et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J Rheumatol2001;28:1330-7.OpenUrlFREE Full Text?Javaid MK, Lynch JA, Tolstykh I, Guermazi A, Roemer F, Aliabadi P, et al. Pre-radiographic MRI findings are associated with onset of knee symptoms: the most study. Osteoarthritis Cartilage2010;18:323-8.OpenUrlCrossRefMedlineWeb of Science?Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M. Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. Ann Rheum Dis2011;70:60-7.OpenUrlFREE Full Text?Peterfy CG, Gold G, Eckstein F, Cicuttini F, Dardzinski B, Stevens R. MRI protocols for whole-organ assessment of the knee in osteoarthritis. Osteoarthritis Cartilage2006;14(suppl A):A95-111.OpenUrlMedlineWeb of Science?Conaghan PG, Felson D, Gold G, Lohmander S, Totterman S, Altman R. MRI and non-cartilaginous structures in knee osteoarthritis. Osteoarthritis Cartilage2006;14(suppl A):A87-94.OpenUrlMedlineWeb of Science?Neogi T, Zhang Y. Osteoarthritis prevention. Curr Opin Rheumatol2011;23:185-91.OpenUrlCrossRefMedline?Yusuf E, Bijsterbosch J, Slagboom PE, Rosendaal FR, Huizinga TW, Kloppenburg M. Body mass index and alignment and their interaction as risk factors for progression of knees with radiographic signs of osteoarthritis. Osteoarthritis Cartilage2011;19:1117-22.OpenUrlCrossRefMedlineWeb of Science?Szebenyi B, Hollander AP, Dieppe P, Quilty B, Duddy J, Clarke S, et al. Associations between pain, function, and radiographic features in osteoarthritis of the knee. Arthritis Rheum2006;54:230-5.OpenUrlCrossRefMedlineWeb of Science?Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum2011;63:691-9.OpenUrlCrossRefMedlineWeb of Science?Neogi T, Felson D, Niu J, Nevitt M, Lewis CE, Aliabadi P, et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ2009;339:b2844.OpenUrlFREE Full Text?Chou R, Fu R, Carrino JA, Deyo RA. Imaging strategies for low-back pain: systematic review and meta-analysis. 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Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study | BMJ

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Research Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study BMJ 2012; 345 doi: 10.1136/bmj.e5253 (Published 21 August 2012) Cite this as: BMJ 2012;345:e5253 Immunology (including allergy) Infectious diseases Sexual health Article Related content Article metrics UK Collaborative Group on HIV Drug ResistanceCorrespondence to: D Dolling, UK HIV Drug Resistance Database, MRC Clinical Trials Unit, London WC2B 6NH, UK David.dolling{at}ctu.mrc.ac.ukAccepted 14 July 2012AbstractObjective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom.

Design Multicentre observational study.

Setting All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care.

Participants 14?584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009.

Main outcome measure Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization.

Results 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively).

Conclusions The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.

IntroductionCombination antiretroviral therapy continues to be highly effective in treating HIV-1, and the introduction of new drugs and antiretroviral drug classes has notably improved patient prognosis. Nevertheless, resistance to antiretroviral drugs can develop in people on therapy and is associated with treatment failure.1 Against this backdrop, the rate of new HIV-1 infections within the United Kingdom continues to rise.2 In such new infections, transmitted drug resistance is sometimes assumed to reflect only direct infection from patients already receiving antiretroviral therapy. Concerns about an adverse effect of transmitted HIV-1 drug resistance on the success of antiretroviral therapy have led to national and international guidelines recommending that all newly diagnosed patients have resistance tests conducted to aid selection of first line regimens.3 4

A previous study showed a sharp decline in the prevalence of transmitted HIV-1 drug resistance in the UK between 2002 and 2005,5 which was mainly attributed to changes in testing guidelines and the wider use of regimens that suppress viral concentrations to below infectious levels. Since then, more potent and better tolerated antiretroviral drugs have been introduced, and the proportion of patients achieving viral suppression has continued to increase.6 This suggests that transmitted HIV-1 drug resistance may have declined even further and could eventually fall below levels in which universal testing before antiretroviral therapy is cost effective,7 an important issue at a time when the cost of HIV-1 management is being scrutinised.8 This paper examines recent time trends in transmitted drug resistance in HIV-1 infections probably acquired in the UK.

MethodsResistance dataThe UK HIV Drug Resistance Database, described in detail elsewhere,9 was established in 2001 and collects the majority of genotypic resistance tests done within the UK as part of routine clinical care. The resistance tests analysed in this study used bulk sequencing of the pol gene, encoding at least codons 4-99 of the protease gene and 34-234 of the reverse transcriptase gene, using a variety of inhouse and commercial testing systems. Subtype was assigned centrally using the Rega algorithm.10

Clinical dataWe acquired demographic and clinical information by linkage (using pseudonymised identifiers) to the UK Collaborative HIV Cohort Study (UK CHIC),9 which includes patients from 13 of the largest clinics within the UK, and to the HIV and AIDS Patient and the Survey of Prevalent HIV Infections Diagnosed databases, which are coordinated by the Health Protection Agency. When possible, we linked resistance tests done after 2007 to samples on which a recent infection testing algorithm had been conducted as part of a national health surveillance programme11; these tests use antibody avidity assays to classify infections as either recent (probably occurring in the previous five months) or non-recent;12 and clinical, laboratory, or historical information to reduce the false recent rate.

Tests included in analysis and definition of drug resistanceThe UK has several parallel and largely non-overlapping HIV-1 epidemics with different levels and patterns of resistance to antiretroviral therapy.13 14 To simplify the understanding of temporal trends, we limited this analysis to subtype B viral infections, so it is not intended to generate nationally representative results. This epidemic was seeded by around six introductions to the UK in the early to mid-1980s15 and is largely confined to men infected through homosexual exposure, of whom 83% are estimated to have acquired infection within the UK.16

We identified the first resistance test for all patients older than 16 years who had not yet received antiretroviral therapy at the time of sampling, up to the end of 2009. Patients with an undetectable viral load (<50 copies/mL) were excluded; such levels may indicate unrecorded treatment use. Since guidelines in 2001 first recommended that resistance tests be performed for all patients who had not received antiretroviral therapy,3 we excluded tests conducted before 2002.

Transmitted HIV-1 drug resistance was defined as one or more mutations from the surveillance list recommended by the World Health Organization.17 We used the Stanford HIVdb algorithm 6.0.11 (29 Mar 2011) to examine susceptibility to antiretroviral drugs, and reported low level resistance or greater. Intermediate or high level resistance was considered to reflect a substantial loss in susceptibility. We assessed temporal trends in terms of the date of the resistance test sample rather than the date of the patient’s infection, which is generally not known.

Statistical methodsConfidence intervals for proportions were calculated using a 95% Wilson confidence interval for binomially distributed data. We analysed the patterns of trends over continuous time using both linear and piecewise linear logistic regression with a flexible choice of a single inflexion point calculated using least squares optimisation; we selected the model with the best fit according to Akaike’s information criterion. The trends for codons were reported if a mutation had an overall prevalence of more than 0.3% as well as other mutations for nucleos(t)ide reverse transcriptase with a strong effect on phenotype (K65R, K70E, L74I/V, Y115F). We examined differences between the prevalence of resistance in recent and non-recent infections tests using the ?2 test. All statistical analyses were conducted in Stata/IC 11.2 software.

ResultsPopulation characteristicsWe analysed 14?583 patients who were antiretroviral therapy naive, infected with a subtype B virus, and whose first drug resistance test was conducted between January 2002 and December 2009. Of these patients, 10?173 (70%) were white, 995 (7%) were black, 711 (5%) had a known other ethnicity, and 2704 (19%) had an unknown ethnicity. The median age at diagnosis was 36 years (interquartile range 30 to 42). Of the patients analysed, 10?288 (71%) were men who had sex with men, 1275 (9%) had a heterosexual exposure source, 313 (2%) had a known other exposure source, and 2707 (19%) had an unknown exposure source. The median number of days between HIV-1 diagnosis and resistance sample was 22 (interquartile range five to 358). The median CD4 count at the time of testing, available from 11?219 (76.9%) patients, was 408×106 cells/L (interquartile range 271×106 to 560×106).

The number of resistance tests conducted per year increased over time, reflecting a rise in the number of new diagnoses among men who have sex with men (fig 1?). The decline between 2008 and 2009 is mainly due to an increase in the proportion of tests where the patient’s status regarding antiretroviral therapy exposure was uncertain (15.6% in 2008 to 32.0% in 2009), probably as a result of a reporting lag with demographic and clinical datasets.

View larger version:In a new windowDownload as PowerPoint SlideFig 1 Prevalence of transmitted drug resistance over time, by antiretroviral drug class. Bar=95% confidence interval

Trends in transmitted drug resistanceSamples from 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance. Of these samples, 1009 (6.9%, 6.5% to 7.3%), 604 (4.1%, 3.8% to 4.5%), and 319 (2.2%, 2.0% to 2.4%) had one or more mutations associated with nucleos(t)ide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Of these samples, 1426 (9.8%, 9.3% to 10.3%) had single class resistance, 175 (1.2%, 1.0% to 1.4%) had dual class resistance, and 52 (0.4%, 0.3% to 0.5%) had triple class resistance; dual and triple class resistance have remained at a similar prevalence since 2005.

The previously reported5 decline in the prevalence of transmitted HIV-1 drug resistance for any class of antiretroviral drug was observed to continue from 15.5% in 2002 until around January 2007 (95% confidence interval January 2006 to February 2008; odds ratio 0.88 per year (95% confidence interval 0.84 to 0.92); fig 1). However, between 2007 and 2009, we saw a non-significant increase from 9.6% to 10.9% (odds ratio 1.06, 0.97 to 1.17; P=0.21). We saw non-significant increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009; P=0.24) and protease inhibitors (1.5% to 2.1%; P=0.12). Inflection points were also identified, which gave a significantly better fit for mutations associated with nucleos(t)ide reverse transcriptase inhibitors (February 2007 (January 2006 to March 2008); second piece odds ratio 1.08 (0.95 to 1.22)) and protease inhibitors (June 2008 (August 2007 to June 2009); 1.69 (0.86 to 3.31)). The prevalence of mutations associated with non-nucleoside reverse transcriptase inhibitors remained stable at around 3.6% with no evidence of non-linearity (odds ratio 0.96 (0.92 to 1.00)).

The table? displays the resistance trends over time for key individual codons with prevalence greater than 0.3%. The trends in HIV-1 drug resistance associated with nucleos(t)ide reverse transcriptase inhibitors largely reflect the most common mutations within this drug class, namely, the T215 revertant18 mutations (I/S/C/D/V/E), K219Q/E/N/R, and M41L. These mutations are either reversions or a subset of the thymidine analogue mutations that develop under regimens containing either stavudine or zidovudine. The finding of a levelling off in the prevalence of thymidine analogue mutations is paradoxical, in the light of the dramatic fall in the use of stavudine and zidovudine. For example, in the UK CHIC study, the proportion of treatment regimens that included stavudine dropped from 29.4% to 0.8% between 2002 and 2009, while the proportion that included zidovudine dropped from 47.9% to 8.8% over the same period. Stavudine and zidovudine have largely been replaced by tenofovir and abacavir,3 but signature mutations for these drugs (such as K65R) are still rare in patients with HIV-1. L90M mutations have increased in prevalence since 2007, despite the near cessation in the use of saquinavir, nelfinavir, and indinavir, which are first generation protease inhibitors that select for this mutation (their use in the UK as part of a drug regimen fell from 20.6% in 2002 to 4.6% in 2009), although L90M has broad cross resistance effects to the protease inhibitor class.19

View this table:View PopupView InlineTime trends of selected mutations with prevalence greater than 0.3%. Data are no (%) of samples with mutation unless stated otherwise

Drug susceptibilityFigure 2? shows the predicted susceptibility of HIV-1 from samples collected in 2009 to currently recommended first line antiretroviral drugs3 and second generation antiretroviral drugs darunavir and etravirine. The association between genotypic mutations and the phenotypic susceptibility to antiretroviral drugs is complex, so although T215 revertants are considered by the Stanford HIVdb algorithm to result in only low level resistance to nucleos(t)ide reverse transcriptase inhibitors, they do confer a low genetic barrier to the development of high level resistance to this drug class.

View larger version:In a new windowDownload as PowerPoint SlideFig 2 Predicted susceptibility to antiretroviral drugs

The prevalence of intermediate or high level resistance to nucleos(t)ide reverse transcriptase inhibitors other than zidovudine was less than 0.9%, reflecting the low frequency of multiple mutations in thymidine analogues. There was a comparatively high level of reduced susceptibility to recommended first line regimens of the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine (3.7%). However, etravirine, a non-nucleoside reverse transcriptase inhibitor, displayed very low levels of resistance (0.4%), reflecting the lack of predicted effect of K103N. The potency of modern drugs from the protease inhibitor class was high (only 25 (1.1%) patients had substantially reduced susceptibility to any protease inhibitor), owing to the rarity of multiple protease mutations. These findings indicate that potent first line regimens can still be constructed from the original three drug classes for almost all patients.

Prevalence of resistance in recently infected patientsBetween 2007 and 2009, 742 samples were linked to a recent infection test result, of which 171 (23.0%) were classified as recent. The overall prevalence of resistance did not differ significantly (P=0.66) between recent samples (20, 11.7%) or non-recent samples (60/571, 10.5%). Furthermore, we detected no significant differences in the prevalence of resistance by individual drug class (results not shown).

DiscussionInterpretationThe previously observed decline in the prevalence of transmitted drug resistance in subtype B viruses seems to have been reversed for mutations associated with nucleos(t)ide reverse transcriptase inhibitors and protease inhibitors, despite an increase in the proportion of patients on antiretroviral therapy who are virologically suppressed (from 62% in 2000 to 84% in 20076). The most frequent mutations were T215 revertants, which may be transmitted as such or evolve from a virus harbouring a T215F or T215Y mutation.19 These and other mutations are associated with a significantly higher risk of virological failure than wild type genotypes.1 17 The prevalence of transmitted thymidine analogue mutations remained moderately high, despite a marked shift away from the prescribing in the UK of drugs that select for these mutations.

One plausible explanation for this paradox is the onward transmission of resistant viruses from people who have not received antiretroviral therapy before and who were themselves infected with a resistant virus. This hypothesis is supported by a previous phylogenetic analysis of UK subtype B sequences, which described five transmission clusters comprised exclusively of patients with resistance mutations who are antiretroviral therapy naive.20 It was postulated that an increasingly greater proportion of transmitted HIV-1 drug resistance could originate from antiretroviral therapy naive lineages, and that there could ultimately be a limit in the decline of transmitted HIV-1 drug resistance.

The first factor contributing to this possible limit is that people with undiagnosed HIV could disproportionally21 spread the epidemic, since they are more infectious in the period immediately after infection.22 Some studies23 24 (but not all25) have also shown that undiagnosed patients with HIV have more sexual partners than diagnosed patients. Furthermore, evidence is emerging that transmitted resistant viruses are more persistent than originally thought. The fitness cost (relative to wild type virus) of certain mutations, such as the T215 revertants and K103N, has been shown to be marginal in laboratory studies.26 27 Jain and colleagues provided clinical confirmation of this finding in a series of patients infected with resistant virus and who had two or more resistance tests before they started antiretroviral therapy.28 With the exception of the M184V mutation, which is highly replicatively deficient, all groups of transmitted mutations persisted beyond at least three years in the majority of patients.

A second possible explanation for the continued prevalence of thymidine analogue mutations is that the use of tenofovir and abacavir are maintaining the prevalence of such mutations in patients who have received antiretroviral therapy despite the decline in the use of zidovudine and stavudine. Further phylogenetic research could shed light on the transmission dynamics of these mutations.

Comparison with other studiesTwo recent studies have reported on time trends in transmitted HIV drug resistance. In a study conducted in 20 European countries between 2002 and 2006,29 Vercauteren and colleagues found a small, linear decline in levels of nucleos(t)ide reverse transcriptase inhibitor and protease inhibitor resistance; non-nucleoside reverse transcriptase inhibitor resistance was observed to increase followed by a decrease between 2004 and 2006. Bartmeyer and colleagues30 performed a similar analysis of a German seroconverter cohort between 1996 and 2007. In more recent years, resistance to nucleos(t)ide reverse transcriptase inhibitors seemed to be stable and resistance to non-nucleoside reverse transcriptase inhibitors seemed to increase, although clear patterns are difficult to discern due to the relatively small sample size.

Study limitationsOur study has several limitations. Firstly, the analysis is based on resistance found at date of sample rather than date of infection. Since viral quasi-species harbouring resistance mutations may revert to, or be overgrown by, virus without the mutations,19 29 the true level of transmitted HIV drug resistance may have been under-estimated in this analysis. Also, the degree of this bias will be affected by the average time between HIV-1 infection and diagnosis, which may have changed over time. Furthermore, the diagnosis delay could mask the underlying trend in the prevalence of transmitted resistance by date of infection. However, we found no difference in the prevalence of resistance between recent and non-recent infections, in the subset of patients in which this analysis was possible.

Secondly, the genotypic data analysed were generated by population sequencing with a limit of sensitivity of approximately 15 to 25%.31 32 Our estimates of the prevalence of transmitted HIV drug resistance may therefore be biased downwards. This will have also biased the type of mutations observed, with persistent mutations appearing to be more prevalent than those which rapidly become undetectable such as K65R or M184V. We do not consider this limitation to be a major concern, because the main objective of our study was to examine changes in the prevalence of transmitted HIV drug resistance over time.

Another limitation was that our method of classifying treatment status could have resulted in misclassification bias if some patients who had received antiretroviral therapy were included in the analysis. Previous research by the UK HIV Drug Resistance Database has suggested that this effect could distort trends if there is misclassification in 4% or more of the samples analysed.33 Finally, as the prevalence of transmitted HIV drug resistance in subtype B viruses, the focus of this analysis, is known to be higher than that observed in other subtypes,34 our findings are not generalisable to the UK epidemic as a whole, although coverage of patients infected with subtype B virus is high.

Conclusions and policy implicationsFinally, we consider the clinical implications of our main conclusion that resistant lineages may have become fixed in the circulating viral pool. This concept, if confirmed to be correct, will apply universally, particularly in countries where first generation nucleos(t)ide reverse transcriptase inhibitors continue to be used, and underscores the importance of sentinel surveillance. In terms of the UK (and probably other well resourced countries), the detectable mutations that tend to be transmitted should have little effect on nucleos(t)ide reverse transcriptase inhibitors currently used in first line regimens, that is, abacavir, tenofovir, lamivudine, and emtricitabine. Non-nucleoside reverse transcriptase inhibitors used in first line regimens are of greater concern, with approximately 4% of patients being infected with viruses with reduced susceptibility to efavirenz and nevirapine. Previous models7 have suggested that baseline resistance testing remains cost effective at the levels observed in this study. Therefore, our findings argue that testing at HIV diagnosis and continued monitoring should remain the standard of care.

What is already known on this topicTransmitted HIV drug resistance can affect therapy success

Some resistance mutations could persist more than others in the absence of selective drug pressure

A 2007 paper has shown a reduction in transmitted drug resistance in the UK since 2005

What this study addsTransmitted drug resistance is no longer declining in UK, and evidence suggests a sustained epidemic that is resistant to nucleos(t)ide reverse transcriptase inhibitors, irrespective of previous antiretroviral therapy use

Susceptibility to antiretroviral therapy remains relatively high, and potent first line regimens can still be constructed from the original three drug classes for almost all patients

NotesCite this as: BMJ 2012;345:e5253

FootnotesThe UK Collaborative Group on HIV Drug Resistance is a collaboration between the UK HIV Drug Resistance Database; UK CHIC; Health Protection Agency HARS; and participating academic centres, clinics, and laboratories.

Analysis/writing group: David Dolling, Caroline Sabin, Valerie Delpech, Erasmus Smit, Anton Pozniak, David Asboe, Andrew Leigh Brown, Duncan Churchill, Ian Williams, Anna Maria Geretti, Andrew Phillips, Nicola Mackie, Gary Murphy, Hannah Castro, Deenan Pillay, Patricia Cane, David Dunn. David Dolling is the guarantor.

Steering Committee: Celia Aitken, Gartnavel General Hospital, Glasgow; David Asboe, Anton Pozniak, Chelsea and Westminster Hospital, London; Clare Booth, Royal Free NHS Trust, London; Patricia Cane, Health Protection Agency, Porton Down; Hannah Castro, Jonathan Crofts, David Dunn (co-chair), David Dolling, Esther Fearnhill, Kholoud Porter, MRC Clinical Trials Unit, London; David Chadwick, South Tees Hospitals NHS Trust, Middlesbrough; Duncan Churchill, Brighton and Sussex University Hospitals NHS Trust; Duncan Clark, St Bartholomew’s and The London NHS Trust; Simon Collins, HIV i-Base, London; Valerie Delpech, Health Protection Agency, Centre for Infections, London; Anna Maria Geretti, University of Liverpool; David Goldberg, Health Protection Scotland, Glasgow; Antony Hale, Leeds Teaching Hospitals NHS Trust; Stéphane Hué, University College London; Steve Kaye, Imperial College London; Paul Kellam, Wellcome Trust Sanger Institute and UCL Medical School; Linda Lazarus, Expert Advisory Group on AIDS Secretariat, Health Protection Agency, London; Andrew Leigh-Brown, University of Edinburgh; Nicola Mackie, Imperial NHS Trust; Chloe Orkin, St. Bartholomew’s Hospital, London; Philip Rice, St George’s Healthcare Trust, London; Deenan Pillay (co-chair), Andrew Phillips, Caroline Sabin, University College London Medical School; Erasmus Smit, Health Protection Agency, Birmingham Heartlands Hospital; Kate Templeton, Royal Infirmary of Edinburgh; Peter Tilston, Manchester Royal Infirmary; William Tong, Guy’s and St. Thomas’ NHS Foundation Trust, London; Ian Williams, Mortimer Market Centre, London; Hongyi Zhang, Addenbrooke’s Hospital, Cambridge; Mark Zuckerman, King’s College Hospital, London.

Centres contributing data: Clinical Microbiology and Public Health Laboratory, Addenbrooke’s Hospital, Cambridge (Jane Greatorex); HIV/GUM Research Laboratory, Chelsea and Westminster Hospital, London (Adrian Wildfire); Guy’s and St. Thomas’ NHS Foundation Trust, London (Siobhan O’Shea, Jane Mullen); HPA – Public Health Laboratory, Birmingham Heartlands Hospital, Birmingham (Erasmus Smit); HPA London (Tamyo Mbisa); Imperial College Health NHS Trust, London (Alison Cox); King’s College Hospital, London (Richard Tandy); Medical Microbiology Laboratory, Leeds Teaching Hospitals NHS Trust (Tony Hale, Tracy Fawcett); Specialist Virology Centre, Liverpool (Mark Hopkins, Lynn Ashton); Department of Clinical Virology, Manchester Royal Infirmary, Manchester (Peter Tilston); Department of Virology, Royal Free Hospital, London (Clare Booth, Ana Garcia-Diaz); Edinburgh Specialist Virology Centre, Royal Infirmary of Edinburgh (Jill Shepherd); Department of Infection and Tropical Medicine, Royal Victoria Infirmary, Newcastle (Matthias L Schmid, Brendan Payne); South Tees Hospitals NHS Trust, Middlesbrough (David Chadwick); St George’s Hospital, London (Phillip Hay, Phillip Rice, Mary Paynter); Department of Virology, St Bartholomew’s and The London NHS Trust (Duncan Clark, David Bibby); Molecular Diagnostic Unit, Imperial College, London (Steve Kaye); University College London Hospitals (Stuart Kirk); West of Scotland Specialist Virology Lab Gartnavel, Glasgow (Alasdair MacLean, Celia Aitken, Rory Gunson).

Coordinating centre: Medical Research Council Clinical Trials Unit, London (Kate Coughlin, Jonathan Crofts, David Dolling, David Dunn, Esther Fearnhill, Kholoud Porter).

Funding: This work was supported by the UK Medical Research Council (grant G0900274) and the European Community’s 7th framework programme (FP7/2007-2013) under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; project 223131).

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from the UK Medical Research Council and the European Community’s 7th framework programme; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: This study was approved by the UK multicentre research ethics committee and relevant local research ethic committees.

Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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