the use of highly active antiretroviral therapy ( haart ) has dramatically improved the quality of life and overall survival of adults and children infected with hiv-1 . however , suboptimal exposure to haart ( e.g. due to poor adherence , inadequate dose ) can rapidly select for drug resistance mutations , and ultimately lead to virological failure . given the dynamics of hiv viral evolution , almost complete ( > 95% ) adherence to combination therapy is required to maximally suppress viral load and avoid selection of resistant strains . moreover , children and adolescents seem to be more prone to selection of drug resistant variants for both biological and behavioral reasons . loss of adherence , long lasting exposure to drugs and multi - drug resistance can determine a more difficult scenario to manage a therapeutical failure than in adults . we describe a 15-year - old caucasian male , with vertically acquired hiv-1 infection , who failed several lines of antiretroviral therapies . he was born premature , at 22week of gestation , with a spontaneous delivery , to a mother who did not assume any therapy during pregnancy . he was started monotherapy with zidovudine in 1993 , didanosine in 1994 , restarted zidovudine in 1995 , and then was treated with stavudine in 1996 . all antiretroviral therapies were done without compliance by the mother - side and were discontinued by her after some months . in 1997 , the patient started the first protease inhibitor ( pi ) based haart with ritonavir plus zidovudine plus lamivudine , without immuno - virological response . the same happened with all the others regimens ( table 1 ) . in the end , he had failed four ritonavir - boosted pibased and one nevirapine - based haart . the patient 's viral load had never been suppressed from his birth , his cd4 cells count nadir was 67 cells/l ( 5.4% ) and his viral load zenith was 89,700 copies / ml . summary of haart regimens and genotypic resistance tests of the patient r : ritonavir ; grt : genotypic resistance test ; rtrm : reverse transcriptase mutations ; pirm : protease mutations plasma hiv-1 rna was measured at baseline and during therapy using a commercial assay , the versant hiv-1 rna 3.0 assay ( bdna ; siemens medical solutions diagnostics , malvern , pa ) , with a dynamic range of 50 - 500,000 hiv-1 rna copies / ml . cd4 cells count was determined by direct immunofluorescence in flow cytometry ( beckman coulter , fullerton , ca ) . genetic analysis of the pol gene including both hiv-1 reverse transcriptase ( codons 4 - 99 ) and protease ( codons 35 - 247 ) regions was performed using the trugene hiv-1 genotyping kit ( siemens medical solutions diagnostic ) . in january 2008 , his clinical conditions were good , cdc status b2 ( bacterial pneumonia ) , and height 167 cm , weight 54 kg , and body mass index ( bmi ) 19.36 . his viral load was 89,700 copies / ml and the cd4 cells count was 287 cells/l ( 16% ) . the genotype revealed the presence of d67n , k70r , y181c , m184v , t215f , k219q mutations within transcriptase and l10i , i13v , l24i , l33f , e34q , m36l , f53l , i54v , l63p , g73s , v82a , n83d mutations within protease genes ( table 1 ) . in summary , there were multiple drug resistance ( mdr ) mutations , which conferred high - level resistance to most currently available antiretroviral agents , included class - resistance to the non - nucleoside reverse transcriptase inhibitors ( nnrtis ) . in that period there was also a change in his family situation : the mother , who had been in jail for 6 months , was released and began to be compliant to her therapy . therefore , after deep counseling to him and the mother , we decided to prescribe a new haart . darunavir / ritonavir and etravirine were provided for compassionate use by tibotec ( cork , ireland ) and their use was approved by san martino hospital ethical committee ( genoa , italy ) . after one month of therapy , viral load became undetectable for the first time in the patient 's life . during the first year of follow - up , viral load remained stably undetectable , meanwhile cd4 cells count and percentage increased to 706 cells / ml and 18% , respectively . in particular , median aspartate aminotransferase ( ast , normal range , r , 0 - 40 ) was 33 u / l , alanine aminotransferase ( alt , r 0 - 40 ) 23 u / l ,  glutamyltranspeptidase ( ggt , r 11 - 50 ) 28 u / l , plasma glucose ( r 65 - 110 ) 83 mg / dl , glycated haemoglobin ( r 4.3 - 5.8 ) 5.1% , insulin levels ( r 2.0 - 25 ) 5.8 mu / l , triglycerides ( r 4 - 170 ) 110 mg / dl , total cholesterol ( r 130 - 200 ) 177 mg / dl , hdl - cholesterol 31.5 mg / dl , and ldl - cholesterol 118 mg / dl . the new regimen was well tolerated and adherence to treatment was reported excellent throughout the entire period , monitored by performing monthly outpatient 's visit and calling the patient every two weeks . strategies for the management of hiv - infected patients with extensive previous treatment and drug resistance are very limited , especially in children and adolescents . as a matter of fact , in this population the use of experimental agents , with a close follow - up , must be considered . this case report has examined the successful inhibition of viral replication in a mdr patient who exhibited very poor compliance with previous therapies . the treatment regimen consisted of a new and recently approved combination used in adults , based on darunavir / ritonavir and etravirine , in addition to a well - known nucleoside reverse transcriptase inhibitor backbone . in the first year of therapy the cd4 cells count increased and viral load fell to undetectable levels . this antiretroviral regimen has been chosen in consequence of the poor compliance of the patient showed during the past years . abacavir seemed to maintain a partial activity , at least according to some interpretation alghorithms , and was preferred to tenofovir which would have been a safer choice based on mutational pattern , by reason of previously tested poor tolerability ( proteinuria ) . darunavir , in combination with low - dose ritonavir , approved in adult since july 2007 in italy , has shown potent antiviral activity and good tolerability in threeclass - experienced hiv - infected patients with limited or no treatment options . recent reports have highlighted that 11 mutations of which 5 major ( i50v , i54l / m , l76v and i84v ) and 6 minor ( v11i , v32i , l33f , i47v , g73s and l89v ) , selected in patients failing it , are associated with decreased susceptibility to darunavir . in our patient the presence of three minor mutations ( l33f , g73s and l89v ) had not compromised the efficacy of the drug . this fact , probably , confirms the importance of number , type , pattern of association and weight of mutations . etravirine , currently available in italy only in the expanded access program ( tmc125-c214 ) , is a second generation nnrti that appears to be effective against a variety of hiv viruses that are resistant to efavirenz and nevirapine . there was only one mutation ( y181c ) , but with a weight factor of 2.5 , using the weighted genotypic score . this score has been provided by vingerhoets j et al . analyzing the database of the patients enrolled in the duet-1 and duet-2 trials . the sum of the different weighted factors predicts virological response to etravirine , and in our patient this should have been an intermediate response . one of the first studies , assessing the role of etravirine and darunavir in hiv-1-infected subjects with no treatment options , showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions . enfuvirtide could be another good choice , also because it is approved for pediatric use , but its way of administration , with often - intolerable subcutaneous injection site reactions , would have never been accepted from the patient . the genotypic test showed also a susceptibility to tipranavir ( one major i54v and one accessory mutation l33f ) , confirmed from the tipranavir - mutation - score ( score = 1 ) that could allow us to choose that drug in the new regimen . we decided , however , to choose darunavir , because etravirine should not be administered with tipranavir . in conclusion , this case report underlines the importance of the continuous development of new drugs and the great need of their approval also for pediatric / adolescent use , as clinicians will continue to encounter an increasing number of mdr hiv - infected youths , who have extensive experience with previous treatments . it is , indeed , of extreme importance to evaluate the compliance with all the available methods ( e.g. self reporting calendars , records of missed doses , pill counts , interview questionnaires , therapeutic drug monitoring ) , knowing that the most common cause of treatment failure is insufficient adherence , which can be found in 25 - 30% of children . in particular , adolescents with vertically acquired - hiv - infection may require complicated regimens , because of significant antiretroviral treatment experience and poor adherence . so it is clear the importance of having parents and/or caregivers who can do an accurate and consistent monitoring and improve the children / adolescent 's compliance .
multiclass - drug resistance , often caused by poor treatment compliance , is a challenging problem in all categories of hiv - infected patients . 
 selective pressure is higher in youth for both biological and behavioral reasons . 
 we report the case of a 15-year - old caucasian male , with vertically acquired hiv-1 infection , who failed several lines of antiretroviral therapy and was successfully treated with darunavir / ritonavir and etravirine .