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Highly active antiretroviral therapy


Rita Murri

BMJ 2005;330;681-682
doi:10.1136/bmj.330.7493.681

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Saturday 26 March 2005

BMJ
Highly active antiretroviral therapy
Exhaustion of treatment options is a challenge that can be delayed

A
Papers p 695
n HIV infected person can possibly live a recourse to active drugs in case of failure of treatment
normal lifespan today, provided she or he needs to be preserved, and drugs that are likely to
takes highly active antiretroviral therapy and induce mutations across classes need to be avoided in
takes it perfectly. As pointed out by Sabin et al in this the beginning. Meanwhile, we need to take the conven-
issue,1 even though new drugs are available each year, ience of patients into account. This would mean few
a noteworthy proportion of people are at risk of pills, few doses, absence of food restrictions, and few
exhausting their treatment options. This proportion is adverse events. After starting treatment, efforts for
only an imperfect surrogate of the presence of assessing and managing side effects should be
mutations giving rise to resistance to antiretrovirals. supported.
For an increasing number of patients, identifying a new We need to implement prolonged and multidimen-
regimen that could lower the HIV viraemia, increase sional interventions for maintaining or increasing
the CD4 cell count, and prevent clinical progression is adherence to drugs. More use of therapeutic drug
somewhat complicated. Looking at reasons why a cur- monitoring in treating HIV infected people may also
rent regimen is no longer working may help to make help identify people at risk of drug failure earlier. After
the available options clearer. treatment failure, easy access to resistance testing and
Suboptimal adherence to treatment is the most the availability of expert guidance have been shown to
common and crucial reason for failing an antiretroviral save some active therapeutic options.10
regimen. Taking treatment at the correct time, not The optimal time to switch from a failing regimen
missing doses or drug holidays, and respecting food is unknown. Patients with detectable but low levels of
restrictions is difficult. Currently treatment needs to be HIV viraemia do not have worse clinical or
taken for life, and such treatment influences everyday immunological outcomes than patients who maintain
life a lot. Even if adherence levels are nearly perfect the undetectable levels of viraemia, even in people who
likelihood of developing resistance to drugs is high.2 have received all three antiretroviral classes of
Intolerance is another reason for failing a drugs.11 12 When HIV changes and becomes resistant to
regimen.3 Side effects may be directly responsible for some drugs, it sometimes loses its capacity to replicate.
suboptimal adherence.4 However, using self reports for This is particularly true with protease inhibitors and
the assessment of symptoms and of the impact that with some nucleoside reverse transcriptase inhibitors
symptoms have on quality of life is uncommon. Often that cause HIV to develop the M184V mutation. We
doctors are unable to predict the frequency and inten- need to find out if after treatment failure, delaying the
sity of adverse events,5 particularly when a regimen change in treatment when HIV viraemia is below
includes three or more different drugs. 10 000 copies/ml and the CD4 cell count remains sta-
So how and when can the rapid exhaustion of ble over time may help to save therapeutic options
treatment options be prevented? This can be without the risk of developing dangerous drug
attempted at any time during the treatment and even resistance.
before starting it. In recent years, difficulties in Preventing the exhaustion of therapeutic options
adherence, toxicity, and the consequent risk of drug for HIV infected people is currently a major challenge
resistance have induced HIV experts and clinicians to for both providers and researchers because all these
postpone the optimal time for starting highly active strategies need a large amount of resources. Finally, to
antiretroviral therapy.6 The fact that immune function maximise the opportunity for long term efficacy and
can be restored even if treatment is started when the tolerability, the selection of treatment would hinge on
CD4 cell count is very low7 8 supports this conservative the patient’s preferences. Even very potent compounds
strategy. Currently healthcare providers try to delay have a high probability of failure if patients do not find
treatment for as long as possible—until the risk of them convenient and if their quality of life is not
opportunistic infections is too high. An ongoing large preserved.
international clinical trial (the SMART study) is
attempting to identify the best time for starting highly Rita Murri consultant in infectious diseases
active antiretroviral therapy (www.clinicaltrials.gov). Department of Infectious Diseases, Catholic University of Rome,
8-00168, Rome, Italy
The first choice of regimen of highly active antiret-
(ritamurri@libero.it)
roviral therapy is crucial.9 An appropriate sequencing
BMJ 2005;330:681–2 of drugs preserves future options. The chance to have Competing interests: None declared.

BMJ VOLUME 330 26 MARCH 2005 bmj.com 681


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Editorials

1 Sabin CA, Hill T, Lampe F, Matthias R, Baghani S, Gilson R, et al. Treat- 7 Garcia F, De Lazzari E, Plana M, Castro P, Mestre G, Nomdedu M, et al.
ment exhaustion of highly active antiretroviral therapy (HAART) among Long-term CD4+ T-cell response to highly active antiretroviral therapy
individuals infected with HIV in the United Kingdom: multicentre cohort according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr
study. BMJ 2005;330:695-8. 2004;36:702-13.
2 Bangsberg DR, Porco TC, Kagay C, Charlebois ED, Deeks SG, Guzman D, 8 Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, Abrams DI, et al.
et al. Modeling the HIV protease inhibitor adherence-resistance curve by Continued CD4 cell count increases in HIV-infected adults experiencing
use of empirically derived estimates. J Infect Dis 2004;190:162-5. 4 years of viral suppression on antiretroviral therapy. AIDS 2003;17:
3 D’Arminio Monforte A, Cozzi Lepri A, Rezza G, Pezzotti P, Antinori A, 1907-15.
Phillips AN et al. Insights into the reasons for discontinuation of the first 9 Centers for Diseases Control. Report of the NIH panel to define princi-
highly active antiretroviral therapy (HAART) regimen in a cohort of
ples of therapy of HIV infection and guidelines for the use of antiretrovi-
antiretroviral naive patients. I.CO.N.A. Study Group. AIDS 2000;14:
ral agents in HIV-infected adults and adolescents. Morb Mortal Wkly Rep
499-507.
MMWR 1998;47(RR-5):1-41.
4 Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De Longis P, et al.
10 Badri SM, Adeyemi OM, Max BE, Zagorski BM, Barker DE. How does
Self-reported symptoms and medication side effects influence adherence
to highly active antiretroviral therapy in persons with HIV infection. J expert advice impact genotypic resistance testing in clinical practice? Clin
Acquir Immune Defic Syndr 2001;28:445-9. Infect Dis 2003;37:708-13.
5 Justice AC, Rabeneck L, Hays RD, Wu AW, Bozzette SA. Sensitivity, 11 Raffanti SP, Fusco JS, Sherrill BH, Hansen NI, Justice AC, D’Aquila R, et
specificity, reliability, and clinical validity of provider-reported symptoms: al. Effect of persistent moderate viremia on disease progression during
a comparison with self-reported symptoms. J Acquir Immune Defic Syndr HIV therapy. J Acquir Immune Defic Syndr 2004;37:1147-54.
1999;21:126-33. 12 The PLATO Collaboration. Predictors of trend in CD4-positive
6 Guidelines for the use of antiretroviral agents in HIV-1 infected adults T-cell count and mortality among HIV-1-infected individuals with
and adolescents. 29 October 2004. http://aidsinfo.nih.gov/guidelines/ virological failure to all three antiretroviral-drug classes. Lancet 2004;364:
adult/AH_102904.pdf (accessed 10 March 2005). 51-62.

Nurse led care


Determining long term effects is harder than measuring short term costs

W
hat’s the difference between medical and The second study, an evaluation of nurse led inter- Papers p 699 and
nursing care? The answer is not straightfor- mediate care in an acute setting (p 699), represents a Primary care p 707
ward, but shortages in the medical more complex nursing role that demands multifarious
workforce mean that nurses are increasingly called on clinical decisions (although patients reaching interme-
to undertake work that was previously done by doctors diate care have been “filtered” through medical
(such as undertaking surgery,1 prescribing drugs, diagnosis and initial treatments).4 These authors
performing triage in emergency departments), undertook a cost minimisation analysis—they viewed
whereas shortages in the nursing workforce mean that the clinical outcomes in the intermediate care and
healthcare assistants now do many tasks that nurses are standard hospital care arms as equivalent and merely
trained to do. This fluidity in professional roles and totalled up and compared the costs. Walsh et al found,
competencies enables the health workforce to respond as have others,5 that nurse led intermediate care in
to need, but are outcomes for patients being improved? acute settings is more expensive than standard hospital
Do these benefits come at an additional cost, and if so, based care for the inpatient phase, but the longer term
are they worth paying for? costs and benefits are more uncertain.
Over the past decade, research has increasingly Close inspection of the clinical outcomes in the
compared nurse led care with usual care for aspects of trial by Walsh et al6 reveals that patients who received
health care previously delivered by doctors. However, nurse led intermediate care had better functional
nurse led care does not have one meaning. Nurse led outcomes at discharge, although this did not reach
care can be usefully viewed as a continuum with, at one significance. However, this lack of statistical signifi-
end, nurses undertaking highly protocol driven, focused cance is not the same as “no difference” in functional
tasks (cardioversion,2 colposcopy, smoking cessation) outcomes. A meta-analysis of 10 studies of nurse led
and, at the other end, responding to far more diverse intermediate care7 (which includes the Walsh trial6)
challenges in terms of clinical decision making, such as identified a statistically significant benefit of nurse led
first contact care and rehabilitation. The extent to which intermediate care on functional status at discharge, as
doctors’ work can be delegated effectively is likely to be well as reductions in the proportion of patients
influenced, in part, by the type and complexity of the discharged to institutional care and in readmissions.
associated decision tasks. This issue of the BMJ presents This indicates that the increase in functional status may
two economic evaluations of nurse led care—each occu- be clinically (and potentially economically) important
pying a different place on this continuum. The paper by and warrants further study.
Raftery et al (p 707) is an evaluation of nurse led In an editorial in the BMJ Briggs counselled
secondary prevention of coronary heart disease and has against cost minimisation analysis in favour of cost
several strengths, including its basis in a randomised effectiveness analysis since studies are rarely powered
controlled trial with four years’ follow up and a cost to confidently identify clinical equivalence.8 Hence, the
effectiveness analysis.3 The authors conclude that lack of a statistically significant difference in effective-
primary care based, nurse led secondary prevention of ness should not be used as a justification for a cost
coronary heart disease is highly cost effective, since the minimisation analysis. While the higher costs of nurse
cost per patient was only £136 ($260; €195) greater in led intermediate care are due to an increased length of
the intervention group, but the benefits (fewer deaths stay, existing analyses have failed to determine whether
and improvements in medical care and patient lifestyle) these costs are offset by lower costs (of health care and
make this highly worth while, with a cost per quality particularly social care) and health benefits gained in
adjusted life year (QALY) of £1097. the longer term. BMJ 2005;330:682–3

682 BMJ VOLUME 330 26 MARCH 2005 bmj.com

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