EVIDENCE-BASED DERMATOLOGY: RESEARCH COMMENTARY
Breakthrough in the Treatment of Warts?
Sam Gibbs, MD; Ipswich Hospital, Ipswich, England
Commentary on: Treatment of skin papillomas
with topical ␣-lactalbumin–oleic acid
Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AK,
Svanborg C
N Engl J Med. 2004;350:2663-2672
Question: Is ␣-lactalbumin–oleic acid (also known as
HAMLET [human ␣-lactalbumin made lethal to tumor
cells]) effective as a treatment for cutaneous viral warts?
Design: A randomized, placebo-controlled double-
blind trial converting to an open label study after 3
months.
Setting: University dermatology department in Lund,
Sweden.
Patients: Forty adults and children with refractory warts
(defined as “papillomas resistant to conventional treat-
ments”). Nine of the 40 patients were receiving immu-
nosuppressive drugs.
Intervention: An aqueous solution of 0.7mM
␣-lactalbumin–oleic acid was applied to all lesions and
occluded with a hydrocolloid dressing daily for 3 weeks.
An identical-appearing solution of normal saline was used
for patients in the placebo arm. In the much longer open-
label phase of the trial, 34 patients received a further 3
weeks of daily ␣-lactalbumin–oleic acid, and 38 of the
original 40 patients were then followed up for 2 years.
Main Outcome Measures: (1) A reduction in lesion vol-
ume of 75% or more 1 month after the end of treatment;
(2) the resolution of at least 1 lesion 1 month after the
end of treatment.
Results: Twenty of 20 patients and 88 of 92 lesions in
the treatment arm experienced a reduction in lesion vol-
ume of 75% or more during the randomized phase of the
study, whereas in the placebo arm the corresponding fig-
ures were 3 of 20 patients and 15 of 74 lesions (P⬍.001).
At follow-up 2 years after the end of the second, open-
label phase of the study, 83% of the patients treated with
␣-lactalbumin–oleic acid experienced resolution of all
lesions.
Conclusions: “Treatment with ␣-lactalbumin-oleic acid
has a beneficial and lasting effect on skin papillomas.”
Comment
The report of this trial occupied more than 9 pages of
the New England Journal of Medicine along with an edi-
torial comment of just over 3 pages. It therefore ought
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767
©2006 American Medical Association. All rights reserved.
to be something to make us stop and think. The real rea-
son for stopping and thinking, however, may not be the
one the article’s authors originally intended.
The trial used the topical application of an unusual
hybrid molecule (consisting of a combination of ␣-lact-
albumin from human breast milk and oleic acid) that is
said to be lethal to a wide range of transformed cells but
harmless to normal ones. The trial appears to have been
properly randomized and fully blinded by the coding of
identical bottles containing active treatment or placebo
saline solution. This said, the precise method of random-
ization is not clear from the article, and the issue of
whether the treatment and placebo bottles could be dis-
tinguished by odor is not addressed. So far so good, but
there are so many questions about the remaining as-
pects of the trial that it is difficult to see how the au-
thors arrived at such an optimistic conclusion.
Why did the trial revert to an open label design so
early on? The evaluation of the outcome of treatment dur-
ing the randomized part of the trial appears to have taken
place about 1 month after the end of 3 weeks of treat-
ment. In fact, the precise timing of outcome assessment
is far from clear in the report, but a period of 1 or even 2
months is far too short by any reckoning. A more rel-
evant interval would have been 6 months or 1 year. The
2-year follow-up period in the open-label part of this trial
is laudable, but, unfortunately, at this stage, the trial was
nonrandomized, most patients had been switched to ac-
tive treatment, and the data (which actually appear to fa-
vor placebo anyway[see below]) are of little value.
How was the sample size decided upon? If this trial
was designed using a sample size calculation, it is not men-
tioned in the text. The trial was certainly modest in size,
and the resulting data generated from the most relevant
outcome (complete resolution of warts with patients, not
lesions, as the unit of analysis) are again not statistically
very meaningful. In the randomized phase of the trial,
the total resolution of at least 1 lesion occurred in 9 of
20 patients in the treatment arm and in 3 of 20 patients
in the placebo arm (risk ratio, 3.00; 95% confidence in-
terval, 0.95-9.48). In other words, there was a differ-
ence between treatment and placebo, and that differ-
ence appears to favor the active treatment but it is not
statistically significant because the sample size was too
small and the confidence interval too wide. These data
appear in a table in the article but are not commented
on by the authors.
At follow-up 2 years after the end of the second, open-
label phase of the study, 29 of 35 patients treated at any
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stage with ␣-lactalbumin–oleic acid experienced com-
plete resolution of all lesions. This is the 83% success rate
reported by the authors in the abstract. However, closer
examination of the data reveals that at this same stage of
the trial 3 (100%) of the 3 patients who never received
any ␣-lactalbumin–oleic acid also experienced com-
plete resolution. Analyzing these rather curious data to-
gether (29/35 vs 3/3) produces a risk ratio, favoring pla-
cebo, of 0.83 (95% confidence interval, 0.71-0.96)! Both
of these analyses, then, lend no support whatsoever to
the notion that ␣-lactalbumin–oleic acid is an effective
treatment for warts.
What sort of person with warts will rejoice over a
75% reduction in lesion volume? The main point of is-
sue with this trial, though, is its tendency to focus on the
outcome of a reduction in wart volume of at least 75%
rather than the more relevant outcome of complete clear-
ance of warts. The article is furnished with beautiful dia-
grams that demonstrate the active treatment reducing wart
volume over time (although there is no specific time scale
along the x-axis of the graphs) and showing that 100%
of patients in the treatment group experienced a greater
than 75% reduction in wart volume. All this lulls the
reader into the impression that the treatment is effec-
tive. The data analyzed above tell a very different story,
however, and although 100% of the patients had a greater
than 75% reduction in wart volume, only 21% of lesions
in the treatment group resolved completely. The former
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768
©2006 American Medical Association. All rights reserved.
result is highlighted in the abstract; the latter receives no
comment, even in the text of the article. Which is the
more relevant outcome? Surely, anyone can see that for
the person with warts, the only relevant outcome is com-
plete resolution of the warts, with no possibility of
recurrence.
Bottom line: The authors’ conclusion that ␣-lactal-
bumin–oleic acid is a useful treatment for warts does not
appear to have a firm scientific basis when their data are
examined carefully. To rephrase Samuel Johnson’s fa-
mous quip (“Sir, your manuscript is both good and origi-
nal, but the part that is good is not original and the part
that is original is not good”), in this trial the clinically
relevant data are not statistically meaningful, and the sta-
tistically meaningful data are not clinically relevant. If
the appropriate outcome is considered, and clear objec-
tive analyses are carried out within the limitations of the
design of the trial, there is no convincing evidence that
␣-lactalbumin–oleic acid is an effective treatment for
warts. The most surprising thing is how this trial man-
aged to be given so much space in such an eminent
journal.
Accepted for Publication: October 25, 2005.
Correspondence: Sam Gibbs, MD, Department of Der-
matology, Ipswich Hospital, Heath Road, Ipswich IP4 5PD,
Suffolk, England (Sam.Gibbs@ipswichhospital.nhs.uk).
Financial Disclosure: None.
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