patient 1 was diagnosed with hiv infection in 2005 at 13 years of age . since the age of 8 , he had complained of a persistent , nonitchy skin rash covering his face and arms .
there was no family history of skin disease and no other past medical history of note .
a physical examination revealed widespread flat , nonscaly , hypopigmented macules from 1 to 15 mm .
the lesions were distributed on the sun - exposed areas of his upper torso , face , neck , and forearms . the genital area , other mucous membranes , scalp , and nails were unaffected .
no specific treatment was available . in july 2005 , he commenced combination antiretroviral therapy ( cart ) with nevirapine , lamivudine , and stavudine .
his nadir cd4 t - cell count was 193 cells/l ( 8% of the total lymphocyte count ) .
after starting cart , his cd4 t - cell count improved to 964 cells/l ( 25% of the total lymphocyte count ) in 2008 and he remained clinically well .
figure 1.ad , physical examination of all 4 cases revealed multiple hypopigmented papules distributed on the trunk , neck , face , and upper limbs .
d , physical examination of all 4 cases revealed multiple hypopigmented papules distributed on the trunk , neck , face , and upper limbs .
patient 2 was found to be infected with hiv in 2005 , at the age of 12 . since 2001 at age 8 , he complained of a persistent nonitchy hypopigmented rash covering sun - exposed areas , including the legs , but with no genital lesions .
the nadir cd4 t - cell count at that time was 186 cells/l ( 11% of the total lymphocyte count ) .
sixteen months later , he was clinically well and his cd4 t - cell count had improved to 479 cells/l ( 23% ) .
the skin eruption remained unchanged despite the introduction of cart ( figure 1b 
 ) .
patient 3 was diagnosed with hiv infection in 2007 at the age of 15 . since the age of 7 , he had complained of a persistent maculopapular eruption similar in distribution and morphology to patients 1 and 2 .
he commenced cart in december of 2007 with a nadir cd4 t - cell count of 180 cells/l . in 2011 ,
his cd4 t - cell count was 414 cells/l and his skin manifestations remained unchanged ( figure 1c ) .
patient 4 was found to be infected with hiv in 2002 when he was 13 years old , following a diagnosis of pulmonary tuberculosis . at that time , disseminated flat warts were noted involving the face and limbs with scattered truncal lesions ; these had been present for several years .
he commenced cart in 2006 , but the nadir cd4 t - cell count was not recorded . in 2010 ,
his cd4 t - cell count was 97 cells/l and the skin rash remained unchanged ( figure 1d 
 ) .
all 4 patients were vertically infected with hiv : all were maternal orphans , denied previous sexual intercourse , and reported no blood transfusions or intravenous drug use .
diagnostic punch skin biopsies were taken from each patient with informed consent ( table 1 ) .
the samples were split : one half was processed for light microscopy and the other half was fixed in formalin for transport , and then rinsed in phosphate buffered saline at 4c before homogenization .
tissue was digested with a 200  g / ml solution of proteinase k overnight at 37c , and dna was extracted using phenol / chloroform and ethanol precipitation . 

table 1.human papillomavirus types isolatedpatientsite of skin biopsyhpv typeshpv type summary/ev typescutaneous wart  associated typesgenital typeshpv types with highest signal intensities ( quantitative and semiquantitative data)1neck51 , 26 , 16 , 18 , 45 , 52 , 53 , 54hpv 1 + + + 




 hpv 2 + + 




 hpv 6 + 2shoulder5,191 , 26 , 11 , 16 , 18 , 31 , 33 , 52hpv 1+++ 




 hpv 2++3arm51 , 26 , 11 , 16 , 31 , 51 , 52 , 66hpv 1+++ 




 hpv 2++4neck51 , 26 , 11 , 16 , 18 , 31 , 52 , 53 , 66hpv 1+++ 




 hpv 2++ 




 hpv 6+abbreviations : ev , epidermodysplasia verruciformis ; hpv , human papillomavirus .
human papillomavirus types isolated abbreviations : ev , epidermodysplasia verruciformis ; hpv , human papillomavirus .
two comprehensive hpv typing systems were utilized in 2 separate specialist hpv research laboratories that could identify cutaneous wart  associated hpv types ,  ( ev - associated ) types , and genital hpv types .
first , polymerase chain reaction ( pcr ) was performed , followed by sequencing using primers that amplify a wide spectrum of hpv types ; pgmy , gp5+/gp6 + , cp65/cp70 , cp66/cp70 , and ch1f / cn1r [ 12 ,  13 ] .
next , confirmatory hpv typing was done using a luminex - based system ( cutaneous hpv ) and 2 reverse hybridization line probe assays ( lipa ) ( genital and -hpv ) [ 1416 ] .
the final hpv typing outcome was obtained by combining the results of all the methods used .
hpv viral load assays were available for common  and genital hpv types ( hpv 5 and hpv 6 , 11 , 16 , and 18 , respectively ) .
diagnostic punch skin biopsies were taken from each patient with informed consent ( table 1 ) .
the samples were split : one half was processed for light microscopy and the other half was fixed in formalin for transport , and then rinsed in phosphate buffered saline at 4c before homogenization .
tissue was digested with a 200  g / ml solution of proteinase k overnight at 37c , and dna was extracted using phenol / chloroform and ethanol precipitation . 

table 1.human papillomavirus types isolatedpatientsite of skin biopsyhpv typeshpv type summary/ev typescutaneous wart  associated typesgenital typeshpv types with highest signal intensities ( quantitative and semiquantitative data)1neck51 , 26 , 16 , 18 , 45 , 52 , 53 , 54hpv 1 + + + 




 hpv 2 + + 




 hpv 6 + 2shoulder5,191 , 26 , 11 , 16 , 18 , 31 , 33 , 52hpv 1+++ 




 hpv 2++3arm51 , 26 , 11 , 16 , 31 , 51 , 52 , 66hpv 1+++ 




 hpv 2++4neck51 , 26 , 11 , 16 , 18 , 31 , 52 , 53 , 66hpv 1+++ 




 hpv 2++ 




 hpv 6+abbreviations : ev , epidermodysplasia verruciformis ; hpv , human papillomavirus .
human papillomavirus types isolated abbreviations : ev , epidermodysplasia verruciformis ; hpv , human papillomavirus .
two comprehensive hpv typing systems were utilized in 2 separate specialist hpv research laboratories that could identify cutaneous wart  associated hpv types ,  ( ev - associated ) types , and genital hpv types .
first , polymerase chain reaction ( pcr ) was performed , followed by sequencing using primers that amplify a wide spectrum of hpv types ; pgmy , gp5+/gp6 + , cp65/cp70 , cp66/cp70 , and ch1f / cn1r [ 12 ,  13 ] .
next , confirmatory hpv typing was done using a luminex - based system ( cutaneous hpv ) and 2 reverse hybridization line probe assays ( lipa ) ( genital and -hpv ) [ 1416 ] .
the final hpv typing outcome was obtained by combining the results of all the methods used .
hpv viral load assays were available for common  and genital hpv types ( hpv 5 and hpv 6 , 11 , 16 , and 18 , respectively ) .
the histological findings in each patient s biopsy included basket - weave orthokeratosis overlying a prominent granular cell layer .
acanthosis , mild spongiosis , focal lymphocyte exocytosis , koilocytes , and occasional prickle layer keratinocytes with enlarged nuclei were also observed .
these histological appearances are those of a plane wart as is typically seen in epidermodysplasia verruciformis ( figure 2 ) . 

the features are those of a plane wart , which is a classic histological feature of epidermodysplasia verruciformis .
the features are those of a plane wart , which is a classic histological feature of epidermodysplasia verruciformis .
hpv 5 , a -type ( ev - associated ) hpv , was detected in all biopsy samples by lipa , but very low copy numbers were detected by real - time quantitative pcr .
multiple cutaneous wart  associated and genital hpv types were also isolated from each sample ( table 1 ) .
hpv types 1 and 2 , usually found in plantar warts , were isolated in all samples with both pcr / sequencing and luminex techniques ; all samples had high hpv 1 signals .
a large number of genital hpv types were identified ( 7 or 8 in each sample ) .
hpv viral load testing was available for hpv 6 , 11 , 16 , and 18 .
however , only hpv 6 was found in levels above the detectable limit in samples from patients 1 and 3 ; the copy number was too low to permit accurate quantification .
the histological findings in each patient s biopsy included basket - weave orthokeratosis overlying a prominent granular cell layer .
acanthosis , mild spongiosis , focal lymphocyte exocytosis , koilocytes , and occasional prickle layer keratinocytes with enlarged nuclei were also observed .
these histological appearances are those of a plane wart as is typically seen in epidermodysplasia verruciformis ( figure 2 ) . 

the features are those of a plane wart , which is a classic histological feature of epidermodysplasia verruciformis .
the features are those of a plane wart , which is a classic histological feature of epidermodysplasia verruciformis .
hpv 5 , a -type ( ev - associated ) hpv , was detected in all biopsy samples by lipa , but very low copy numbers were detected by real - time quantitative pcr .
multiple cutaneous wart  associated and genital hpv types were also isolated from each sample ( table 1 ) .
hpv types 1 and 2 , usually found in plantar warts , were isolated in all samples with both pcr / sequencing and luminex techniques ; all samples had high hpv 1 signals .
a large number of genital hpv types were identified ( 7 or 8 in each sample ) .
hpv viral load testing was available for hpv 6 , 11 , 16 , and 18 .
however , only hpv 6 was found in levels above the detectable limit in samples from patients 1 and 3 ; the copy number was too low to permit accurate quantification .
we describe acquired ev in 4 adolescents with longstanding , untreated vertically acquired hiv infection .
in addition to identifying  expected  ev - associated -hpv types in skin biopsies from affected areas , hpv types 1 and 2 were detected in each biopsy , as well as 7 or more hpv types normally associated with genital lesions . despite immune reconstitution with cart
, there was no improvement in the ev lesions , from which multiple hpv strains were isolated after several years of otherwise successful treatment .
hpv 1 and 2 , classically associated with plantar warts , were also isolated in skin biopsies from our patients , together with hpv 5 , commonly found in patients with congenital ev .
hpv 3 , a cutaneous wart  associated hpv type , has previously been identified in ev lesions from 1 hiv - infected individual ; by contrast , hpv 1 or 2 have not been described .
hpv infection is frequent in immunocompromised patients , but there are few reports of ev occurring in acquired immunodeficiency states [ 410 ] . prior to this study ,
only 18 cases of hiv - associated ev have been reported , and only 2 described congenital hiv and ev [ 10 ,  19 ] .
one of these 2 patients was found to be homozygous for the c912a t polymorphism in the tmc8/ever2 gene .
more than 100 hpv types are recognised and classified into 3 clinical categories : anogenital or mucosal , cutaneous wart  associated , and -hpv types .
classical ev results from a cell - mediated immune deficiency and an accompanying underlying genetic susceptibility to ev - hpv .
this results in an inhibition of natural cytotoxic mechanisms against hpv - infected keratinocytes , leading to the development of skin lesions .
thus , is it possible that these 4 long - term survivors had an undefined , underlying genetic susceptibility , but it is more likely that they had a long - standing , acquired cell - mediated immune defect secondary to a chronic , untreated hiv infection .
these vertically hiv - infected adolescents probably first experienced hpv infection in early childhood when their cell - mediated immune systems were already impaired by hiv , whereas adults who are infected with hiv later in life have robust immune mechanisms against hpv infection that were developed in childhood when their immune systems were still intact .
this might explain why ev is not as common in hiv - infected adults as it is in older hiv - infected children .
close contact between these immunosuppressed children and other hpv - infected children in an hiv clinic or with hiv - infected adults with multiple hpv types is a possible explanation for the unusually high number of genital and nongenital hpv types isolated in each skin biopsy .
laboratory contamination is an unlikely explanation for the detection of hpv types 19 , 45 , 51 , 52 , 53 , 54 , and 66 , as these types were not stored in the 2 research laboratories .
lee et al   reviewed the treatment of twenty patients with congenital ev and concluded that oral retinoids ( with or without interferon ) were effective , as was low - dose oral retinoid maintenance .
relapses were common upon treatment cessation and caution is advised when prescribing retinoids to adolescents with child - bearing potential due to the recognized teratogenicity .
topical imiquimod , intralesional interferon , 5-fluorouracil , and cimetidine have all been used as treatment , but with variable success [ 1 ,  6 ,  8 ,  10 ] .
previous reports suggest that treatment of hiv - associated ev is less successful than that for classical ev .
a recent treatment trial of glycolic acid in hiv - positive children in botswana showed a trend toward flattening and color normalization in flat warts , although complete resolution was observed in only 10% of patients .
response was greatest in those developing warts after starting art and those with fewer hpv types . in this
resource - limited setting , alternative treatments were not available and immune reconstitution with cart had no impact on the appearance of the lesions .
this group of adolescents was left with a disfiguring and potentially stigmatizing condition in high - prevalence communities where the skin condition is frequently identified as being associated with hiv infection .
classical ev is associated with a high risk of lesional transformation to squamous cell carcinoma , occurring in up to 70% of cases
malignant lesions usually occur in the third and fourth decades of life , but there are case reports of carcinoma appearing as early as 15 and 17 years of age .
the oncogenic potential of hpv 5 and 8 is well established but other ev - hpv , including hpv 10 , 14 , 20 , and 47 , have also been implicated [ 18 ,  22 ] .
both ultraviolet b and diagnostic x - ray radiation have been identified as oncogenic cofactors in hpv 5related malignancies [ 1 ,  22 ] .
no malignancies were encountered in our series or other reported cases of hiv - associated ev , but as cart becomes more widely available , adolescents surviving to adulthood will need close dermatological surveillance .
this is particularly important among this group of children with longstanding immune deficiency and high levels of sun exposure . in summary , we describe 4 hiv - infected adolescents with ev - like lesions .
preliminary results suggest that among long - term survivors of vertically - acquired hiv , this might be a common clinical hpv phenotype .
it is a disfiguring condition and difficult to treat because no impact on the progression of skin disease has been observed after the administration of cart .
ev is relatively rare in hiv - infected adults but appears to be frequent in vertically - infected children , and close dermatological surveillance for potential skin malignancy is required .
 we have characterized the ev - like dermatosis of acquired hiv in 4 adolescents . 
 multiple hpv types were isolated in skin tissue samples , including -hpv , but also high levels of hpv 1 and 2 . 
 arv did not improve the ev eruption . 