Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up

BMC Infectious Diseases

Elizabeth A Reddy²  Coleen K Cunningham¹  Aisa M Shayo³  Dorothy E Dow³ 

[1] Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA;Division of Adult Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA;Kilimanjaro Christian Medical Centre, Moshi, Tanzania

关键词: Viral load;    Durability of antiretroviral therapy;    HIV RNA;    ART adherence;    Thymidine analogue mutations;    HIV resistance;    Pediatric HIV;   

Others  :  1125397
DOI  :  10.1186/s12879-014-0567-3

 received in 2014-04-08, accepted in 2014-10-16,  发布年份 2014

【 摘 要 】

Background

In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up.

Methods

This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained.

Results

161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01).

Conclusions

After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.

【 授权许可】

   
2014 Dow et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]UNAIDS Report: Together we will end AIDS. UNAIDS, Geneva, Switzerland; 2012.
• [2]Fund UNC’s: Towards an AIDS-Free Generation – Children and AIDS: Sixth Stocktaking Report, 2013. UNICEF, New York; 2013.
• [3][http://who.int/hiv/pub/guidelines/arv2013/arvs2013upplement_march2014/en/] webcite World Health Organization. March 2014 Supplement to the 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Recommendations for a public health approach. 2014. Genieva, Switzerland. Available at:Last accessed 7 August 2014.
• [4]Fitzgerald F, Penazzato M, Gibb D: Development of antiretroviral resistance in children with HIV in low- and middle-income countries. J Infect Dis 2013, 207(Suppl 2):S85-92.
• [5]Barth RE, Tempelman HA, Smelt E, Wensing AM, Hoepelman AI, Geelen SP: Long-term outcome of children receiving antiretroviral treatment in rural South Africa: substantial virologic failure on first-line treatment. Pediatr Infect Dis J 2011, 30(1):52-56.
• [6]Boyd MA, Kumarasamy N, Moore CL, Nwizu C, Losso MH, Mohapi L, Martin A, Kerr S, Sohn AH, Teppler H, Van de Steen O, Molina JM, Emery S, Cooper DA: Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013, 381(9883):2091-2099.
• [7]Bartlett JA, Ribaudo HJ, Wallis CL, Aga E, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Kallungal BA, Kumarasamy N: Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. Aids 2012, 26(11):1345-1354.
• [8]Jourdain G, Le Coeur S, Ngo-Giang-Huong N, Traisathit P, Cressey TR, Fregonese F, Leurent B, Collins IJ, Techapornroong M, Banchongkit S, Buranabanjasatean S, Halue G, Nilmanat A, Luekamlung N, Klinbuayaem V, Chutanunta A, Kantipong P, Bowonwatanuwong C, Lertkoonalak R, Leenasirimakul P, Tansuphasawasdikul S, Sang AGad P, Pathipvanich P, Thongbuaban S, Wittayapraparat P, Eiamsirikit N, Buranawanitchakorn Y, Yutthakasemsunt N, Winiyakul N, Decker L, et al.: Switching HIV treatment in adults based on CD4 count versus viral load monitoring: a randomized, non-inferiority trial in Thailand. PLoS medicine 2013, 10(8):e1001494.
• [9]Mugyenyi P, Walker AS, Hakim J, Munderi P, Gibb DM, Kityo C, Reid A, Grosskurth H, Darbyshire JH, Ssali F, Bray D, Katabira E, Babiker AG, Gilks CF, Grosskurth H, Munderi P, Kabuye G, Nsibambi D, Kasirye R, Zalwango E, Nakazibwe M, Kikaire B, Nassuna G, Massa R, Fadhiru K, Namyalo M, Zalwango A, Generous L, Khauka P, Rutikarayo N: Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet 2010, 375(9709):123-131.
• [10]Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P, Nahirya-Ntege P, Bakeera-Kitaka S, Thomason M, Bwakura-Dangarembizi M, Musiime V, Munderi P, Naidoo-James B, Vhembo T, Tumusiime C, Katuramu R, Crawley J, Prendergast AJ, Musoke P, Walker AS, Gibb DM: Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet 2013, 381(9875):1391-1403.
• [11]Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR: Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc 2012, 15(2):17427.
• [12]De Luca A, Hamers RL, Schapiro JM: Antiretroviral treatment sequencing strategies to overcome HIV type 1 drug resistance in adolescents and adults in low-middle-income countries. J Infect Dis 2013, 207(Suppl 2):S63-69.
• [13]Emmett SD, Cunningham CK, Mmbaga BT, Kinabo GD, Schimana W, Swai ME, Bartlett JA, Crump JA, Reddy EA: Predicting virologic failure among HIV-1-infected children receiving antiretroviral therapy in Tanzania: a cross-sectional study. J Acquir Immune Defic Syndr 2010, 54(4):368-375.
• [14][http://hivdb.stanford.edu/] webcite Stanford University Drug Resistance Database. Accesssed March 24, 2014
• [15]Kekitiinwa A, Asiimwe AR, Kasirye P, Korutaro V, Kitaka S, Maganda A, Madalon M, Graziano FM: Prospective long-term outcomes of a cohort of Ugandan children with laboratory monitoring during antiretroviral therapy. Pediatr Infect Dis J 2012, 31(8):e117-125.
• [16]Buchanan AL, Montepiedra G, Sirois PA, Kammerer B, Garvie PA, Storm DS, Nichols SL: Barriers to medication adherence in HIV-infected children and youth based on self- and caregiver report. Pediatrics 2012, 129(5):e1244-1251.
• [17]Williams PL, Storm D, Montepiedra G, Nichols S, Kammerer B, Sirois PA, Farley J, Malee K, Team PC: Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics 2006, 118(6):e1745-1757.
• [18]Chandwani S, Koenig LJ, Sill AM, Abramowitz S, Conner LC, D'Angelo L: Predictors of antiretroviral medication adherence among a diverse cohort of adolescents with HIV. J Adolesc Health 2012, 51(3):242-251.
• [19]Nachega JB, Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, Cotton M, Maartens G: Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern Africa. J Acquir Immune Defic Syndr 2009, 51(1):65-71.
• [20]Bygrave H, Mtangirwa J, Ncube K, Ford N, Kranzer K, Munyaradzi D: Antiretroviral therapy outcomes among adolescents and youth in rural Zimbabwe. PloS one 2012, 7(12):e52856.
• [21]Evans D, Menezes C, Mahomed K, Macdonald P, Untiedt S, Levin L, Jaffray I, Bhana N, Firnhaber C, Maskew M: Treatment outcomes of HIV-infected adolescents attending public-sector HIV clinics across Gauteng and Mpumalanga, South Africa. AIDS Res Hum Retroviruses 2013, 29(6):892-900.
• [22]Lowenthal ED, Bakeera-Kitaka S, Marukutira T, Chapman J, Goldrath K, Ferrand RA: Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges. Lancet Infect Dis 2014, 14(7):627-639.
• [23]Bratholm C, Johannessen A, Naman E, Gundersen SG, Kivuyo SL, Holberg-Petersen M, Ormaasen V, Bruun JN: Drug resistance is widespread among children who receive long-term antiretroviral treatment at a rural Tanzanian hospital. J Antimicrob Chemother 2010, 65(9):1996-2000.
• [24]Musiime V, Kaudha E, Kayiwa J, Mirembe G, Odera M, Kizito H, Nankya I, Ssali F, Kityo C, Colebunders R, Mugyenyi P: Antiretroviral drug resistance profiles and response to second-line therapy among HIV type 1-infected Ugandan children. AIDS Res Hum Retroviruses 2013, 29(3):449-455.
• [25]Hosseinipour MC, Gupta RK, Van Zyl G, Eron JJ, Nachega JB: Emergence of HIV drug resistance during first- and second-line antiretroviral therapy in resource-limited settings. J Infect Dis 2013, 207(Suppl 2):S49-56.
• [26]Sigaloff KC, Ramatsebe T, Viana R, de Wit TF, Wallis CL, Stevens WS: Accumulation of HIV drug resistance mutations in patients failing first-line antiretroviral treatment in South Africa. AIDS Res Hum Retroviruses 2012, 28(2):171-175.
• [27]Ruel TD, Kamya MR, Li P, Pasutti W, Charlebois ED, Liegler T, Dorsey G, Rosenthal PJ, Havlir DV, Wong JK, Achan J: Early virologic failure and the development of antiretroviral drug resistance mutations in HIV-infected Ugandan children. J Acquir Immune Defic Syndr 2011, 56(1):44-50.
• [28]Murphy RA, Sunpath H, Castilla C, Ebrahim S, Court R, Nguyen H, Kuritzkes DR, Marconi VC, Nachega JB: Second-line antiretroviral therapy: long-term outcomes in South Africa. J Acquir Immune Defic Syndr 2012, 61(2):158-163.
• [29]Gibb DM, Walker AS, Kaye S, De Rossi A, Ait-Khaled M, Pillay D, Munoz-Fernandez MA, Loveday C, Compagnucci A, Dunn DT, Babiker AG: Evolution of antiretroviral phenotypic and genotypic drug resistance in antiretroviral-naive HIV-1-infected children treated with abacavir/lamivudine, zidovudine/lamivudine or abacavir/zidovudine, with or without nelfinavir (the PENTA 5 trial). Antivir Ther 2002, 7(4):293-303.