Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants

Prendergast, Andrew J.; Mphatswe, Wendy; Tudor‐Williams, Gareth; Rakgotho, Mpho; Pillay, Visva; Thobakgale, Christina; McCarthy, Noel D.; Morris, Lynn; Walker, Bruce D.; Goulder, Philip

doi:10.1097/qad.0b013e32830437df

Cited by 76 publications

(72 citation statements)

References 31 publications

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“…The pediatric study cohort has been described previously (26,32). In brief, we enrolled 63 HIV-infected infants born to HIV-infected mothers at St. Mary's and Prince Mshiyeni Hospitals in Durban, South Africa, between 2003 and 2005.…”

Section: Methodsmentioning

confidence: 99%

“…The risk of MTCT is related to viral load in the mother, and a high viral load is associated with nonprotective alleles, such as HLA-B*18 and -B*5802. This may contribute in two distinct ways to the more rapid progression observed in pediatric HIV infection (24,26,27). First, because infected children share 50% or more of their HLA alleles with the transmitting mother, they are less likely than adults to carry protective HLA alleles (16).…”

Section: Human Immunodeficiency Virus (Hiv)-specific Cd8mentioning

confidence: 99%

“…Analyzing a previously described cohort of 61 HIV-infected children in Durban (24,26,32), South Africa, who were all monitored from birth, we first addressed the question of whether possession of any of these four alleles by either mother or child is associated with slower disease progression in the child and then determined whether sharing of protective alleles by mother and child affects the ability of the child to make the Gag-specific CD8 ϩ T-cell responses restricted by the shared allele.…”

Section: Human Immunodeficiency Virus (Hiv)-specific Cd8mentioning

confidence: 99%

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Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection

Thobakgale

Prendergast

Crawford

et al. 2009

J Virol

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A broad Gag-specific CD8؉ T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8؉ T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (P ‫؍‬ 0.007). Slow progressors tended to make CD8 ؉ T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (P ‫؍‬ 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%; P ‫؍‬ 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8 ؉ T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.

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Section: Methodsmentioning

confidence: 99%

Section: Human Immunodeficiency Virus (Hiv)-specific Cd8mentioning

confidence: 99%

Section: Human Immunodeficiency Virus (Hiv)-specific Cd8mentioning

confidence: 99%

See 1 more Smart Citation

Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection

Thobakgale

Prendergast

Crawford

et al. 2009

J Virol

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“…The study cohort has previously been described elsewhere (29,34). Briefly, 63 HIV-infected infants who met the study criteria were randomized at diagnosis to one of three arms: deferred antiretroviral therapy (ART), started once clinical or immunological criteria were reached (arm A), immediate shortterm ART given for 1 year and then stopped (arm B), or immediate short-term ART given with up to three structured treatment interruptions (STIs) to 18 months of age and then stopped (arm C).…”

Section: Methodsmentioning

confidence: 99%

Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate

Prado

Prendergast

Thobakgale

et al. 2010

J Virol

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Human immunodeficiency virus (HIV)-infected infants in the developing world typically progress to AIDS or death within the first 2 years of life. However, a minority progress relatively slowly. This study addresses the potential contribution of viral factors to HIV disease progression in eight infants selected from a wellcharacterized cohort of C clade HIV-infected infants, monitored prospectively from birth in Durban, South Africa. Three infants were defined as "progressors," and five were defined as "slow progressors." We observed that slow-progressor infants carry HIV isolates with significantly lower replicative capacity compared to virus from progressors. Furthermore, our data suggest a link between the attenuated viral phenotype and HLA-B* 57/5801 epitope-specific Gag mutational patterns of the transmitted virus and not to coreceptor usage or to the presence of Nef deletions or insertions. These data underline the importance of virus-host interactions and highlight the contribution of viral attenuation through Gag-specific CD8 ؉ T-cell escape mutations, among other factors, in the control of pediatric HIV infection.

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“…There is strong evidence that the early initiation of ART in HIV-infected children can substantially reduce HIV-related morbidity and mortality. [3][4][5][6] In the guidelines it published in 2010, the World Health Organization (WHO) recommended the immediate initiation of ART upon diagnosis of HIV infection in infants and older children, irrespective of the children's CD4+ T-lymphocyte counts. 7 The early initiation of ART in infants requires reliable early infant diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Early infant diagnosis of HIV infection in Zambia through mobile phone texting of blood test results

Seidenberg

Nicholson²,

Schaefer

et al. 2012

Bull World Health Org

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Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants

Abstract: Excellent adherence and virological suppression are achievable in infants, despite high-frequency NNRTI mutations and rapid disease progression. Infants remain relatively neglected in roll-out programmes and ART provision must be expanded.

Cited by 76 publications

References 31 publications

Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection

Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection

Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate

Early infant diagnosis of HIV infection in Zambia through mobile phone texting of blood test results

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