Antiretroviral-Drug Resistance among Newly HIV-Infected Patients

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					                                                        This Week in the Journal
                                                                                              August 8, 2002




                                                                                       Antiretroviral-Drug Resistance among Newly
                                                                                       HIV-Infected Patients
                                                                                       In a study of 377 patients with newly acquired human immunodefi-
Patients with Resistance (%)




                               20
                                           Nucleoside RT inhibitors
                                           Nonnucleoside RT inhibitors
                                           Protease inhibitors
                                                                                       ciency virus (HIV) infection in 10 cities in North America, the prev-
                               15                                                      alence of antiretroviral-drug resistance increased from 3.4 percent in
                               10
                                                                                       1995 through 1998 to 12.4 percent in 1999 through 2000. The fre-
                                                                                       quency of multidrug resistance at presentation also increased, from
                                5                                                      1.1 percent to 6.2 percent. After initial antiretroviral therapy was ad-
                                                                                       ministered, it took longer to achieve viral suppression in those who
                                0
                                    1995      1996    1997     1998      1999   2000   were infected with resistant virus, and the time to virologic failure in
                                                        Year                           these patients was shorter.

                                                                                       The frequency of drug-resistant virus is increasing among patients
                                                                                       with newly diagnosed HIV infections, reflecting a higher rate of trans-
                                                                                       mission of resistant virus. Drug-resistance testing before treatment
                                                                                       is now indicated even for patients who are newly infected and have
                                                                                       never received antiretroviral therapy.
                                                                                                                              see page 385 (editorial, page 438)




                                                                                       Intramuscular Injection of Botulinum Toxin
                                                                                       for Wrist and Finger Spasticity after a Stroke
                  “Botulinum toxin A                                                   Intramuscular injection of botulinum toxin type A has been used to
                                                                                       treat patients with spasticity after a stroke, but its efficacy remains un-
                  had positive effects on                                              certain. In this randomized, double-blind, placebo-controlled trial in-
                                                                                       volving patients with spasticity after a stroke, one-time injections of
                 functional disability.”                                               botulinum toxin A into wrist and finger muscles with high flexor tone
                                                                                       reduced muscle tone and improved functional disability over a 12-week
                                                                                       period. There were no major adverse effects of botulinum toxin in-
                                                                                       jections.

                                                                                       Treatment with injections of botulinum toxin A in wrist and finger
                                                                                       muscles appears to be safe and effective in the short term, reducing
                                                                                       disability and improving the quality of life in patients with upper-
                                                                                       limb spasticity after a stroke.
                                                                                                                           see page 395 (Perspective, page 382)




Copyright © 2002 Massachusetts Medical Society.                                                  N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org · 381


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                                     The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne



                                          2002, the Food and Drug Admin-              a double-blind, randomized, con-
      PERSPECTIVE                         istration (FDA) approved the use            trolled trial, subjects picked their
                                          of botulinum toxin for the treat-           own “principal target of treatment”:
                                          ment of “frown lines” at the glabel-        hygiene, dressing, pain, or limb pos-
   Stroke, Spasticity,                    la, between and above the eyes. This        ture. Six weeks after the injections,
                                          cosmetic use of the toxin has already       62 percent of the subjects who re-
    and Botulinum                         attracted the interest of countless         ceived botulinum toxin reported
        Toxin                             people who want to look younger.            improvement, as compared with 27
                                          The toxin is also used to erase             percent of those who received pla-
                                          “crow’s feet” — wrinkles at the lat-        cebo. There were no serious adverse


B
       otulinum toxin is in the news      eral margin of each eye.                    effects. The benefits lasted for at
       these days. First came Sep-           In this issue of the Journal, Bra-       least 12 weeks.
       tember 11 and fears of chem-       shear and colleagues (see pages                Each year, approximately 750,000
ical terrorism. One gram of this          395–400) report that local intra-           Americans have a stroke. Roughly
“most poisonous poison” could kill        muscular injections of botulinum            a third die, making stroke the third
a million people were it not for          toxin can ameliorate disability of the      leading cause of death after myo-
problems of delivery. Then, in April      wrist and fingers after a stroke. In        cardial infarction and cancer. An-



    Neuromuscular Junction
                  Axon terminal
                                             Normal                                Action of Botulinum Toxin A
                                        Transmitter Release


                                        Neuron
                       Muscle cell
                                                                             Light chain         Heavy chain


                                       Acetylcholine
                       Synaptic
                        vesicle
                                                                            Botulinum
                                                                           toxin cleaves
                                                                              SNARE
                                                                             proteins
   SNARE                                                                                                        Botulinum
   proteins       Synaptobrevin                                                                                    toxin
                                                                                                                 receptor
    Syntaxin         SNAP 25


                                                    Acetylcholine                                              Botulinum
    Synaptic                                          released                                                  toxin A
      cleft


                                        Acetylcholine
    Muscle cell                           receptor


Acetylcholine in nerve terminals is packaged in vesicles. Normally, vesicle membranes fuse with those of the
nerve terminals, releasing the transmitter into the synaptic cleft. The process is mediated by a series of pro-
teins collectively called the SNARE proteins. Botulinum toxin, taken up into vesicles, cleaves the SNARE pro-
teins, preventing assembly of the fusion complex and thus blocking the release of acetylcholine.




382 · N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org


  Downloaded from www.nejm.org on August 25, 2007 . Copyright © 2002 Massachusetts Medical Society. All rights reserved.
                                             T HIS WEEK IN TH E JOUR NA L




other third recover, and a third are     spasticity because cervical cerebro-      groups of muscles, including bleph-
disabled. Of the approximately           spinal fluid is too close to the brain,   arospasm, hemifacial spasm, cervical
4 million people who have survived       which tolerates baclofen poorly.          dystonia (torticollis), and writer’s
a stroke, many have hemiplegia and       The limitations of oral drug therapy      cramp. These uses of the toxin were
impairment of the hands.                 also apply to spasticity of the legs,     welcomed as major therapeutic ad-
   Two questions arise. To what ex-      which has been treated with intra-        vances in neurology.
tent is disability caused by spastic-    thecal injections of phenol or surgi-        In the past decade, botulinum
ity? Why is botulinum toxin used         cal resection of dorsal nerve roots       toxin has been used to treat spas-
to treat it?                             (rhizotomy) to diminish reflex ac-        ticity caused by cerebral palsy, spi-
   If the corticospinal tracts on one    tivity. The multiplicity of treatments    nal cord injury, multiple sclerosis,
side of the brain are injured, the im-   is ipso facto evidence that there is      and stroke. Injections in leg mus-
mediate effect is contralateral hem-     no optimal treatment. Moreover, al-       cles are said to help relieve bother-
iparesis or hemiplegia. If the injury    though such treatments have led to        some muscle spasms, allow a care-
is mild, there may be serious loss       improvements in measured joint            giver to wash and dress the patient,
of dexterity with only slight weak-      angles or scales of limb mobility, it     and relieve pain.
ness. These are the “negative” ef-       has been difficult to demonstrate            The findings reported by Bra-
fects of upper-motor-neuron le-          functional improvement in walking         shear et al. warrant further study
sions. Immediately or within days,       or use of the hands.                      because questions remain. Which
the “positive” signs appear: over-          Therapeutic use of botulinum           patients are the best candidates for
active tendon reflexes, Hoffmann         toxin bypasses some of these prob-        botulinum toxin? Can functional
and Babinski signs, clonus, and hy-      lems. The toxin prevents acetylcho-       improvement be expected? Will this
pertonia, or increased resistance of     line vesicles from binding with pro-      treatment help patients regain in-
muscle to passive movement. Over         teins needed for fusion to surface        dependence in activities of daily
time, the spasticity may worsen,         membranes and exocytosis. This in-        living? Why did so many patients
causing fixed flexion contractures       hibitory effect reduces the number        have a response to placebo? The
at the elbows, wrists, and fingers.      of presynaptic transmitter vesicles,      appropriate role of botulinum tox-
These complications are the target       impeding neuromuscular transmis-          in in the management of spasticity
of therapy. Spasticity is attribut-      sion and weakening the muscle (see        after stroke will surely be tested in
able to overactivity of monosynap-       Figure). In contrast to treatment         more trials to come.
tic muscle-stretch reflexes, hyperto-    with phenol and rhizotomy, the
nia, or both.                            effects of botulinum toxin are not                     LEWIS P. ROWLAND, M.D.
   William Landau, in Clinical Neu-      permanent, persisting only until             Columbia–Presbyterian Medical Center
romythology and Other Arguments          new neuromuscular junctions are                             New York, NY 10032
and Essays, Pertinent and Imperti-       formed in weeks or months. And
nent (Armonk, N.Y.: Futura, 2001),       in contrast to drug therapy, which
argues that disability in these cir-     may induce sedation or somno-
cumstances arises from the negative      lence, injections of toxin have only
symptoms, not from spasticity. It        local effects.
is fruitless, he concludes, to expect       The use of botulinum toxin to
functional improvement from the          treat neurologic disease dates back
treatment of spasticity. Yet there is    to around 1970, when the toxin was
a huge literature on anti-spasticity     used to reduce the overactivity of
treatments. Physical therapy is one      extraocular muscles in patients with
approach. Another is the adminis-        strabismus. This approach was ap-
tration of baclofen or tizanidine to     proved by the FDA in 1989 and
reduce spinal cord reflex activity.      rapidly replaced muscle surgery,
Taken by mouth, however, baclofen        which had previously been the
has limited effectiveness. Therefore,    standard treatment. By 1990, bot-
implanted pumps have been used           ulinum toxin had also been used —
to deliver baclofen directly to the      successfully and safely — to treat
cerebrospinal fluid. This approach       involuntary-movement disorders at-
is not an option for treating hand       tributable to overactivity of local




                                                    N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org · 383


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                                                                                The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne



  “Factors other than                                                                Variant Cystic Fibrosis Phenotypes in the Absence
                                                                                     of CFTR Mutations
mutations in the CFTR                                                                Classic cystic fibrosis is an autosomal recessive disorder that is caused
   gene can produce                                                                  by loss-of-function mutations in the cystic fibrosis transmembrane
                                                                                     conductance regulator (CFTR) gene. Clinical manifestations in the
 phenotypes clinically                                                               airways, pancreas, male reproductive tract, and sweat glands that re-
                                                                                     semble those occurring in classic cystic fibrosis have been observed
indistinguishable from                                                               in patients with mutations that reduce, but do not eliminate, the func-
                                                                                     tion of CFTR protein. This study included 30 patients who had no
nonclassic cystic fibrosis                                                           identifiable CFTR mutations and who had some features of cystic
                                                                                     fibrosis but did not meet a clinical definition of classic cystic fibrosis.
   caused by CFTR                                                                    The authors conclude that this variant phenotype derives from factors
     dysfunction.”                                                                   other than mutations in the CFTR gene.

                                                                                     If reproducible, these findings suggest that a syndrome with many
                                                                                     aspects of cystic fibrosis can arise from mutations in genes other
                                                                                     than CFTR.
                                                                                                                                 see page 401 (editorial, page 439)


                                                                                     Voriconazole for Invasive Aspergillosis
                         100                                                         Invasive aspergillosis is a major infectious complication in patients with
Patients Surviving (%)




                          80
                                                      Voriconazole group             prolonged neutropenia and in transplant recipients, and for decades,
                                                                                     amphotericin has been the standard treatment. This randomized, un-
                          60
                                                      Amphotericin B group           blinded trial involving 391 patients compared voriconazole with am-
                          40                                                         photericin as the initial treatment for invasive aspergillosis. Those
                          20                                                         treated with voriconazole had a significantly better response rate and
                                   P=0.02                                            improved survival at 12 weeks (70.8 percent vs. 57.9 percent,
                           0
                               0      2     4     6        8      10       12        P=0.02).
                                                Weeks

                                                                                     Voriconazole represents a major advance in the treatment of invasive
                                                                                     aspergillosis. In this randomized trial, treatment with voriconazole,
                                                                                     a broad-spectrum triazole, led to improved survival and was better
                                                                                     tolerated than amphotericin, with fewer severe adverse reactions.
                                                                                                                                                     see page 408


                                                                                     Medical Progress: Inflammatory Bowel Disease
                                                                                     Clinical experience has suggested that Crohn’s disease and ulcerative
                                                         Type 1 helper               colitis constitute distinct, if not discrete, entities. However, whether
                                                            T cell                   these conditions are fundamentally different or are part of a mechanis-
                                                                                     tic continuum is a question with both conceptual and practical impli-
                                                                                     cations for management. This review summarizes current understand-
                                                                                     ing of the mechanisms underlying the major forms of inflammatory
                                                                                     bowel disease and discusses approaches to therapy.

                                                                                     Inflammatory bowel disease is the result of inappropriate and ongo-
                                                                                     ing activation of the mucosal immune system fueled by the presence
                                                Antigen-presenting                   of normal luminal flora. This aberrant response appears to be facil-
                                                       cell
                                                                                     itated by defects in both the barrier function of the intestinal epithe-
                                                                                     lium and the mucosal immune system.
                                                                                                                                                     see page 417


384 · N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org


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