Adherence to Guidelines
“When to Start”
“When to start” guidelines at the time of ART initiation were followed for 438 (87.6%) patients (Table 2). Adherence to this guideline was similar in primary care and hospital sites but significantly higher in Melbourne versus Sydney (92.8% vs. 82.4%, respectively; P = 0.0004), mainly driven by higher levels of initiation via clinical trial in the latter city (4.8% vs. 36.0%, respectively; P < 0.0001). Adherence increased over time with adherence rates in periods 1, 2, and 3 being 83.2%, 93.0%, and 86.5%, respectively (P = 0.019 for trend) (Fig. 1).
During period 3 (ie, 2008), when initiating ART at CD4 200–350 cells per cubic millimeter became a strongly recommended guideline (level A), 173 patients commenced ART. After exclusion of 7 patients (including 2 with primary HIV infection) whose CD4+ count rebounded and remained above 350 cells per microliter on retesting, there were 41 patients at the 4 sites who had a CD4 count <350 cells per microliter who did not commence ART. Of these, 14 were lost to follow-up, 11 declined ART despite physician recommendation, 5 commenced ART within 6 months (in early 2009), 10 commenced ART in 2009, 6–12 months after CD4 <350 cells per cubic millimeter, and 1 patient died without commencing ART. Adherence to “when to start” ART reduced adherence to guidelines to 67% when the 41 patients were included in period 3.
Univariable predictors for greater adherence to “when to start” guidelines included variables associated with illness or more advanced HIV disease, including CDC category C, category B, Mycobacterium avium complex testing, lower CD4 count, inpatient ART initiation, lower weight, and older age. Predictors for nonadherence included clinical trial variables such as use of investigational agents, use of raltegravir, having HIV resistance testing and urinalysis. Additionally, nonsmokers, those receiving no concomitant medication, and patient preference as a reason for initiation of ART were each significantly associated with nonadherence.
In multivariable analysis, adherence to “when to start” was less likely in those who initiated ART in a clinical trial and who had previously received short-term nontherapeutic ART (via HIV postexposure prophylaxis or a 2-week pharmacokinetic study) (Table 3).
“What to Start”
Three hundred and forty-five patients (69%) initiated ART with drugs that were included in the guidelines-“preferred” category, and 85.8% of drugs used were classified as either “preferred” and/or “alternative”, increasing to 88.7% after exclusion of patients initiating ART via a clinical trial. Seventy-one patients (14.2%) initiated ART containing at least 1 nonpreferred/alternative drug. One hundred and twenty (93%) of the nonpreferred/alternative drugs were used before later inclusion in the guidelines, whereas 9 (7%) drugs were no longer recommended in the guidelines at the time of ART initiation. Contraindicated or not recommended ART was initiated in 19 (3.8%) patients, most commonly nevirapine in men and women with CD4+ counts >400 and >250 cells per microliter, respectively (13 patients), and atazanavir in patients also receiving a proton pump inhibitor or H2 antagonist (6 patients). No patient-initiated monotherapy or dualtherapy ART, contraindicated combinations of ART, efavirenz during pregnancy, a protease inhibitor although taking simvastatin, abacavir when HLA-B*5701 positive, or ART without lamivudine, emtricitabine, or tenofovir when hepatitis B surface antigen positive.
The changing pattern of ART regimens over time (seeFigure, Supplemental Digital Content 2, http://links.lww.com/QAI/A267) largely reflects the changes in guideline recommendations (Table 3). Dual nucleoside analogue reverse transcriptase inhibitor backbones remain the predominant choice for ART initiation. Coformulated zidovudine–lamivudine use significantly declined over time (P < 0.0001), coformulated abacavir–lamivudine use declined more recently (P < 0.0001), whereas use of coformulated tenofovir–emtricitabine significantly increased (P < 0.0001). Nonnucleoside analogue reverse transcriptase inhibitor use as the third ART drug significantly increased (P = 0.03), due mainly to an increase in efavirenz use. Protease inhibitor use correspondingly declined (P < 0.0001) and, whereas atazanavir use increased, coformulated lopinavir–ritonavir use diminished (P < 0.0001).
Hospital sites were more likely than primary care sites to use “preferred” ART regimens (76.8% vs. 62.2%, P = 0.0002), mainly due to the preference for coformulated abacavir–lamivudine in primary care sites (24.8% vs. 16.0%, P = 0.015). Adherence to “preferred” ART regimens increased significantly in the most recent tertile period with adherence to “preferred ART” of 63.6%, 61.6%, and 83.2% during periods 1, 2, and 3, respectively, (P < 0.0001) (Fig. 1).
Univariable predictors for adherence to “what to start” guidelines-“preferred” drugs included variables consistent with more recent ART initiation date, parameters of more advanced disease such as initiating ART after an AIDS diagnosis, Mycobacterium avium complex testing, lower hemoglobin and lower CD4 percentage. Initiation of ART adherent to “what to start” guidelines was more likely to occur in patients comanaged between Primary Care and Hospital sites, patients assessed for injecting drug use, patients in whom blood pressure, fasting glucose, creatinine, and chest radiograph were performed, and patients with hepatitis B coinfection, but were less likely to have had diet and lifestyle counseling or negative chlamydia and/or gonorrhoea testing. Predictors of nonadherence to “what-to-start” guidelines included HLA B*5701 testing, use of lamivudine in ART initiation (reflecting use of lamivudine with abacavir), and white race (higher in primary care sites).
Adherence to “what to start” using guidelines-preferred drugs on multivariable analysis (Table 3) was more likely with recent initiation of ART and less likely at the Melbourne primary care site.
Adherence to Comorbid Disease Assessment
Comorbid disease assessment guidelines (level AIII) were adhered to variably ranging from 0.8% for TB testing by TB skin test or interferon gamma release assay to 99.2% for full blood count (as measured by white cell count) (Table 2).
Primary care sites were more likely to assess fasting lipids (48.8% vs. 35.6%, P = 0.014), glucose (52.4% vs. 42.4%, P = 0.015), syphilis serology (74.8% vs. 65.6%, P = 0.025), and Pap smears in women (83.3% vs. 30.4%, P < 0.0001). Hospital clinics were more to test for creatinine (94.4% vs. 82.4%, P < 0.0001), toxoplasma serology (64.0% vs. 36.8%, P < 0.0001), and hepatitis B serology (81.2% vs. 45.6%, P < 0.0001). Testing for comorbid diseases was more likely to occur in Sydney than in Melbourne, perhaps reflecting the higher testing rates in patients initiating ART via a clinical trial (Table 2).
Mean adherence to assessment of the 11 AIII comorbid disease parameters (excluding TB testing and Pap smear) was 58.6%. Adherence to each of the 11 comorbid disease parameters that comprised this score ranged from 25.6% (urinalysis) to 99.2% (white blood count). Only 1.6% of patients received all 11 nominated assessments for comorbid diseases.
Seven variables were independently associated with adherence to comorbid disease assessment (Table 3). Significantly greater comorbid assessment was performed in patients who initiated ART in a clinical trial or after an AIDS diagnosis, patients referred to allied health practitioners for diet and lifestyle advice, and patients provided with treatment education although significantly less comorbid disease assessment occurred in primary care sites and patients in whom a smoking history was not collected. Finally, adherence to comorbid disease assessment significantly improved over time (individual comorbid assessments over time can be seen in Supplemental Digital Content 3, http://links.lww.com/QAI/A268).
Adherence to comorbid clusters increased over time but was low for coinfections, renal and CVD risk (Table 2 and Fig. 2). Multivariable predictors for cluster comorbidities (Table 3) showed association of coinfection assessment at hospital sites and in Melbourne and renal and CVD risk assessment in Sydney.
This study is the most comprehensive audit of adherence to DHHS guidelines on initiation of ART and the largest audit of more recent guidelines. Between 2004 and 2008, there was a high level of adherence in the 4 primary care and hospital-based sites in Sydney and Melbourne to the guidelines on “when to start” and “what to start”, and to key guidelines that were strongly recommended and supported by clinical trial evidence. There was more variable adherence to comorbid disease assessment and other recommended guidelines that were based on expert opinion or not categorized.
The adherence to guidelines compares favorably with audits conducted in the United States6,7 and United Kingdom.8–14 An audit in 2001–2002 involving 113 UK sites and 942 patients revealed 89.6% adherence to United Kingdom recommendations for initiating ART.13 However, small numbers of patients were studied at each site, and were unlikely to have been recruited consecutively, and thus may have been a biased sample. A more thorough study of 217 women initiating ART in multiple clinics from 1998 to 2004 was conducted by the WIHS consortium in the United States as follows: 54% of patients met “when to start” criteria whilst 53% met “what to start – preferred or alternative regimen” and a high rate of 17% were initiated on ART that was “not recommended”.6 The WIHS study covers an earlier period of ART initiation than our study, but does contrast with the rates in the Australian sites of 86% meeting “preferred or alternative” ART and 4% meeting “not recommended” therapy.
The high adherence we observed may reflect the geographical and therapeutic concentration of HIV patients in Australia. Most of the 20,000 cases and the approximately 1000 annual new diagnoses are in men who have sex with men living in inner city Sydney and Melbourne.16 Their HIV treatment is managed by high caseload primary care practices and hospital clinics. A key component to achieving high adherence to guidelines has been the restriction of ART prescribing to registered prescribers who participate in ongoing training and education and dispensing of ART by specified hospital outpatient pharmacies. The higher adherence may also be due to the relatively low proportion of patients who actively inject drugs (specific substance not collected) or have socioeconomic disadvantage (not collected in this audit), the universal access to health care and ART, and a relatively high level of HIV experience of treating physicians and restricted prescriber status in Australia. Adherence to guidelines on “what to start” in our study is an underestimate. The overwhelming majority of patients initiating nonrecommended ART did so in clinical trials and received regimens that were subsequently recommended.
The success of ART in suppressing HIV and providing improved prognosis has focused attention on the importance of comorbid diseases in managing patients with HIV.17,18 Our study showed a far lower and more variable adherence to guidelines-recommended comorbid disease assessment than for “what to start” or “when to start”, although there was significant improvement over time. Since the period of ART initiation from 2004 to 2008, awareness of the importance of comorbidities in HIV management has increased and with the greater emphasis on comorbidities such as CVD and renal disease, a greater adherence to monitoring of these conditions is expected. The relatively low level of baseline resistance testing was one of the adverse findings of the audit. HIV resistance in Australia is comparable with other Western countries and given the high use of nonnucleoside reverse transcriptase inhibitors as first-line therapy, this omission will change with the introduction in 2010 of reimbursement for testing in Australia.
One of the limitations of this study is the evaluation of ART initiation at specific high HIV caseload inner city sites where relatively large numbers of HIV patients are treated and may not represent the treatment practices in low caseload and more geographically isolated sites in Australia. In these practices, and in Australia, the majority of patients with HIV are men who have sex with men and have access to healthcare and 63% have some contact with HIV/AIDS organizations.19 Another factor possibly limiting the generalizability of our findings is the greater HIV experience in audit physicians (mean 13.8 years) relative to HIV prescribers (approximately 5 years; unpublished data, Australasian Society of HIV Medicine).
In addition, the characteristics of all patients eligible for treatment, but not initiating ART over the 3 periods, at the study sites was not included, which may bias the results. Inclusion of the 41 patients with CD4 counts <350 cells per microliter, with the 173 patients initiating ART in period 3, reduced the adherence of when to start from 86% to 67%. The Australian HIV Observational Database collected data from 27 Australian clinics on 501 patients initiating ART mainly before 2005,20 and found the median CD4 count in this population was 236 cells per microliter compared with 270 cells per microliter in our audit. It is unknown whether adherence to “what to start” and assessment of comorbid diseases is similar in the Australian HIV Observational Database cohort in comparison to our study.
Experience from this study provides a baseline for further investigation and clarity on the direction of future audits. There were a large number of variables predicting adherence to guidelines, but only a few were related to adherence in multivariable analyses suggesting that these latter variables deserve close attention in any audit, and perhaps in patient care. A more simplified audit is therefore feasible with all sites still focusing on key guidelines but also addressing assessment of comorbid diseases, which have been more variably adhered to in this audit.
Adherence to key treatment guidelines for ART initiation is supported by clinical trial data. A key question remaining, however, is whether adherence to treatment guidelines improves patient outcomes.
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HIV Guidelines Audit Steering Committee: Mark Bloch, Andrew Carr, Nicola Cunningham, Jennifer Hoy, Anna Pierce, Norman Roth, and Jo Watson.
Participating sites, patients. and physicians—Melbourne: The Alfred Hospital: Paul Cameron, Kate Cherry, Suzanne Crowe, Jon Darby, Justin Denholm, Joe Doyle, Julian Elliott, Andrew Fuller, Michelle Giles, Margaret Hellard, Jenny Hoy, Simon Iles, David Iser, Adam Jenney, Stephen Kent, Sharon Lewin, John Mills, Anne Mijch, Orla Morrissey, Jessica Rotty, Joe Sasadeusz, Matthew Skinner, Denis Spelman, Alan Street, Olga Vujovic, Amanda Wade, Steve Wesselingh; Ian Woolley, Edwina Wright, Michelle Yong, Prahran Market Clinic: Drs Mark Choong, Pauline Cundill, Beng Eu, Tek Lim, Mike Porter, Norm Roth, Sven Strecker. Sydney: Holdsworth House Medical Practice: Drs David Austin, Mark Bloch, Andrew Gowers, Hsin Hua Liu, Ercel Ozser, Dick Quan. St Vincent's Hospital: Drs Mark Boyd, Bruce Brew, Andrew Carr, David Cooper, Greg Dore, Anthony Kelleher, Kersten Koelsch, Debbie Marriott, Gail Matthews, Sam Milliken, and Sarah Pett.
Project Manager: N. Cunningham (HHMP).
Site coordinators: S. Agrawal (HHMP), K. Sinn (SVH), H. Lau, and M. Bryant (PMC), C. Rayner, J. Armishaw & A. Pierce (The Alfred).
Statisticians: M. Bailey and N. Andriopoulos.
Gilead Sciences—for unrestricted research grant
antiretroviral therapy; clinical audit; HIV guidelines; HIV comorbidities; initiating ART
Supplemental Digital Content
© 2012 Lippincott Williams & Wilkins, Inc.