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Antiretroviral Treatment of Infected Children in Resource-Limited Settings
HIV InSite's Coverage of the 14th Conference on Retroviruses and Opportunistic Infections
Claire Thorne, MD, University College London

Published March 22, 2007
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Diagnosis of HIV Infection in Exposed Infants
Cotrimoxazole Prophylaxis
Pediatric Issues in Resource-Rich Settings
References
Table 1

A large number of posters presented at CROI addressed the use of antiretroviral (ARV) drugs for pediatric patients in resource-limited settings. The studies highlighted the fact that HIV-infected children in resource-limited settings generally are started on ARVs at older ages and at later stages of HIV disease progression than those in developed countries, but also indicated that they can achieve treatment successes similar to those seen with children in more developed countries.

Kline presented data from the Baylor International Pediatric AIDS Initiative on nearly 10,000 HIV-infected children from 5 programs in Botswana, Uganda, Lesotho, and Malawi. Of the 4,000 children receiving antiretroviral treatment (ART), most started with symptomatic disease between the ages of 5 and 8.(1) In the Botswana program (the longest running), 81% of treated children had undetectable viral loads (<400 copies/mL) at 12 months, decreasing to 71% at 36 months. Approximately 90% of children followed for at least 2 years were alive and on treatment, but 10% of children followed for at least 2 years had switched from first-line regimens.

The KIDS-ART-LINC cohort collaboration reported data on 1-year survival after ART initiation in nearly 2,000 children from 8 centers in southern, western, and central Africa.(2) Median age at initiation of ART was 5.4 years. The cumulative probability of mortality was 3.1% at 3 months after initiation of ART and 4.9% at 12 months. For those <18 months of age, cumulative probability of mortality was 16.8%, decreasing to as low as 1.8% in those starting at later ages. The data demonstrate that ART initiation is a strong predictor of death. The younger the children, the poorer their prognoses. Severe anemia and severe immunodeficiency at the time of ART initiation also were associated with a higher risk of death. No difference was observed in regard to whether the first-line regimen was based on a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).

Jaspan and colleagues described outcomes among nearly 400 South African children starting ART.(3) Comparison of NNRTI-containing ART with PI-containing ART revealed that children on the former were 74% less likely to be virologically suppressed at 24 months of treatment, adjusting for baseline CD4 count, weight Z score, age, and duration of therapy. The authors suggested possible reasons for this finding, including resistance (although no data were presented on exposure to single-dose nevirapine for prevention of mother-to-child transmission of HIV), drug interactions (with antituberculosis therapy), or dosing problems. Of note, there were no differences in CD4 count or growth among the ART groups.

Results on response to ART were reported by Nkengasong and colleagues in a group of 134 ARV-naive children starting ART at a median age of 7, in Abidjan, Cote d'Ivoire.(4) Slightly more than half achieved viral suppression in the first year of therapy, with an overall 11% increase in CD4 percentage. Carter et al presented results on treatment response in a group of about 300 children starting ART (mainly NNRTI containing) at a median of 19 months of age within MTCT-Plus Initiative sites in Africa.(5) The average 6-month increase in CD4 percentage ranged from 10% for children aged <6 months to 14% for those aged 12-35 months. Among 250 children on first-line ART in a Ugandan pediatric cohort, independent predictors of virological failure were male gender (2.5 times increased risk), low baseline CD4 percentage (4 times increased risk with <5% vs >5%), and stavudine-containing regimens (3 times increased risk vs zidovudine-containing regimens).(6)

Several presentations addressed the issue of clinical markers for predicting need for initiation of ART or for predicting mortality. In the 3Cs4kids collaboration, similar to studies in resource-rich settings, CD4 count and CD4 percentage were strong predictors of mortality, whereas total lymphocyte count appeared to be less predictive.(7) Weight for age and hemoglobin level were strong predictors of mortality, independent of CD4 count and percentage. The predictive value of CD4 count and percentage was found to be reduced in children with lower weight for age. Tillekeratne and colleagues investigated 162 infected children in Tanzania, with a median age at presentation of nearly 6 years: 69 children had World Health Organization (WHO) stage 1 or 2 disease, of whom one third progressed to symptomatic disease within 18 months of presentation.(8) Factors at the initial visit that were associated with subsequent clinical progression included CD4 percentage, lymphadenopathy, and weight and height Z scores.

In a pharmacokinetic study of 2 fixed-dose tablets, Pedimune Baby (nevirapine 50 mg + stavudine 6 mg + lamivudine 30 mg) and Pedimune Junior (double Pedimune Baby dose), among infected children in Zambia, Kabamba and colleagues reported that nevirapine concentrations were higher than previously reported in adults, with 7% of children having a subtherapeutic nevirapine Cmin, whereas pharmacokinetic results for stavudine and lamivudine were comparable to those for adult data.(9)

Diagnosis of HIV Infection in Exposed Infants

Various low-cost approaches to the early screening and diagnosis of HIV infection in exposed infants were presented at the conference, including the ultrasensitive p24 antigen (Up24 Ag) assay,(10,11) CD4/CD8 ratio,(12,13) and real-time polymerase chain reaction (PCR) of dried blood spots (DBS).(14) Driver and colleagues evaluated risk of cross-contamination in DNA PCR analysis of DBS, finding an extremely low risk regardless of method (manual punch vs automated punch).(15) Waters and colleagues evaluated filter paper transfer of whole blood and plasma samples for HIV RNA quantification in Uganda, finding that use of plasma was more accurate (fewer false positives) but more expensive and more difficult to perform, as the technique requires centrifugation.(16) Also in Uganda, Downing et al evaluated different approaches (cell pellets, DBS, and plasma) for efficacy in early diagnosis, finding that DBS outperformed cell pellets regarding accuracy in the PCR testing and convenience, but that plasma Up24 Ag was an acceptable alternative.(17)

Cotrimoxazole Prophylaxis

The CHAP trial showed a 43% decline in mortality and a 23% decline in hospital admissions with use of cotrimoxazole prophylaxis for HIV-infected children in Zambia. In an update from this trial, Gibb and colleagues presented cost-effectiveness data showing that cotrimoxazole prophylaxis was highly cost effective, at US$53 per disability-adjusted life year (DALY) averted.(18) They concluded that their results strongly support the adoption of WHO guidelines on the inclusion of cotrimoxazole prophylaxis within essential health care packages in low-income settings. Gasasira presented data on the very successful use of both cotrimoxazole prophylaxis and insecticide-treated bed nets for HIV-infected children in Kampala, Uganda, a malaria-endemic area: after a year, malaria incidence was significantly lower among the infected children than among a community control group of healthy children.(19) In a cohort of 120 infected children in Tanzania, use of cotrimoxazole prophylaxis was significantly associated with reduced likelihood of diarrhea, Cryptosporidium infection, and death.(20)

Pediatric Issues in Resource-Rich Settings

See Table 1 for a summary of pharmacokinetic, safety, and efficacy studies in children.

Treatment interruptions were covered by several posters. In a small case-control study of programmed treatment interruptions as an ARV-sparing strategy, cases (children with good response to first-line ART who interrupted treatment for a median of 36 months) had a progressive significant decline in CD4 count but stable viral load (after the initial rebound) compared with controls; a fifth of them restarted ART with good response.(21) In a study of 40 children with partial treatment interruption of a PI within an ART regimen (median duration of interruption was 45 months), Phillips and colleagues reported that all had reverse transcriptase and PI resistance at baseline, and most (80%) maintained at least 3 primary PI mutations, despite an absence of PI drug pressure, suggesting that maintenance of triple-class resistance can be achieved within simplified regimens.(22)

The contentious issue of the costs and benefits of very early initiation of ART in HIV-infected infants was addressed by Compagnucci and colleagues.(23) They describe the 5-year follow-up of 20 children from the PENTA 7 study who received didanosine + stavudine + nelfinavir at <3 months of age. Although there was good clinical and immunological improvement and no major toxicities reported, viral load was not completely suppressed in all children, which led to the emergence of some resistance mutations. At age 5, only 2 of the children were still on the original regimen and 4 had discontinued drugs permanently. The authors concluded that the issue of long-term toxicity among children exposed very early in life to ART needs further research.

With regard to ART-associated toxicity, Viganò presented data on bone metabolism derangement among 27 vertically infected children and adolescents on long-term ART, and identified an increased bone turnover and marked alteration of bone resorption regulation in these children compared with healthy controls; a switch from stavudine to tenofovir and from a PI to efavirenz restored the equilibrium of receptor activator of nuclear factor-kB (RANKL), an osteoclast formation stimulator.(24)

Two posters indicated that there is a significant risk of mental health problems in HIV-infected children growing into adolescence and young adulthood. Chernoff and colleagues reported on the PACTG1055, a prospective study of psychiatric symptoms in nearly 600 youths, both vertically HIV infected (n = 323; median age: 12.9) and uninfected (n = 259; mean age: 11.3).(25) Infected children were twice as likely as uninfected children to have received psychotropic medications, and more than a third had received such drugs or behavioral interventions for psychiatric symptoms. In another study, Rutstein et al investigated the mental health of a cohort of 136 children with HIV living in the United States.(26) A quarter had previously had at least 1 mental health visit (general population figure for this age group is 6-9%), and 13% were on antidepressants or medication for attention deficit hyperactivity disorder.

Navarro and colleagues investigated HIV/hepatitis C coinfection in a retrospective study of 19 coinfected children (median age: 14 years) enrolled in a large Spanish cohort.(27) Two children received no HIV treatment, and the remaining 17 had an average of 113 months on ART. Two children had received specific hepatitis C treatment. Most children had mild liver fibrosis, but 16% had histological progression.

In a collaboration between the HPPMCS (vertically infected children studies) and CASCADE (an adult seroconverter cohort collaboration), the association of current CD4 count with short-term risk of AIDS and death in infected adults and children aged >5 years was investigated.(28) Children experienced mortality rates similar to those found in adults aged approximately 20 years; at CD4 counts of <150-300 cells/µL, children had a lower risk of progression to AIDS or death than adults, but a higher risk at counts above this range. The authors concluded that their results suggest similar CD4 count criteria for both adults and children >5 years of age can be used for determining when to start ART.

References

  1. Kline M, Anabwani G, Kekitiinwa A, et al. Catalyzing the Care and Treatment of HIV-infected Children in Sub-Saharan Africa: Early Outcomes from 5 Baylor College of Medicine Centers. Abstract 79.
  2. Arrivé E, Marquis B, Tumwesiye N, et al. Response to ART in Children in Sub-Saharan Africa: A Pooled Analysis of Clinical Databases, the KIDS-ART-LINC Collaboration. Abstract 727.
  3. Jaspan H, Berrisford A, Roux P, et al. Outcomes of Children on NNRTI vs PI HAART Regimens in Resource-limited Settings. Abstract 728.
  4. Nkengasong JN, Adje-Toure C, Hanson D, et al. Virologic and Immunologic Response to ART and Predictors of HIV-1 Drug Resistance in Children Receiving Treatment in Abidjan, Côte d'Ivoire. Abstract 729.
  5. Carter R, Katyal M, Austin J, et al. Age and CD4 Percentage at ART Initiation: Relationship to CD4 Response over Time among Children Enrolled in MTCT-Plus Initiative Sites. Abstract 730.
  6. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of Long-term Viral Failure among Ugandan Children and Adults Treated with ART and Monitored Using Clinical and Immunologic Criteria. Abstract 732.
  7. Gibb D, Duong T, 3Cs4kids Cohort Collaboration. Markers for Predicting Mortality in HIV-infected Children in Resource-limited Settings. Abstract 701.
  8. Tillekeratne LG, Feng S, Schimana W, et al. Use of Clinical Markers to Identify Pediatric HIV-infected Patients Who May Benefit from Early Initiation of ART in Northern Tanzania. Abstract 702.
  9. Kabamba D, L'homme R, Ewings F, et al. Pharmacokinetics of Nevirapine, Stavudine, and Lamivudine in HIV-infected Children in Zambia Treated with Pediatric Fixed-dose Combination Tablets. Abstract 580.
  10. Elyanu P, Fiscus S, Ndeezi G, et al. Evaluation of Ultrasensitive p24 Antigen Assay as an HIV Diagnostic Method among HIV-exposed Children Attending Mulago Hospital. Abstract 669.
  11. Sohn A, Le Q, Truong X, et al. The Ultrasensitive p24 Antigen Assay Is Comparable to DNA PCR for Early Infant Diagnosis, Ho Chi Minh City, Vietnam. Abstract 670.
  12. Swaminathan S, Gangadevi P, Perumal V, et al. CD4/CD8 Ratio as a Surrogate Marker for HIV Infection in Infancy. Abstract 685.
  13. Read J, Pahwa S, Yin W, et al. CD4/CD8 Ratio for Diagnosis of HIV-1 Infection in Infants: The Women and Infants Transmission Study. Abstract 686.
  14. Ou CY, Balinandi S, Sawadogo S, et al. Early Diagnosis of HIV-1 Infection in Infants Using Dried Blood Spots and Real-time Polymerase Chain Reaction. Abstract 687.
  15. Driver G, Patton J, Moloi J, et al. Assessing the Risk of Contamination between Samples during Their Excision from Dried Blood Spots for HIV-1 DNA PCR Testing. Abstract 671.
  16. Waters L, Kambugu A, Meya D, et al. Evaluation of Filter Paper Transfer of Dried Whole Blood and Plasma Spots to Monitor the Viral Load of Africans Taking ART. Abstract 674.
  17. Downing R, Homsy J, Elyanu P, et al. Evaluating Testing Strategies for Early HIV Diagnosis in Children. Abstract 684.
  18. Ryan M, Chitah B, Griffin S, et al. The Cost Effectiveness of Cotrimoxazole as Prophylaxis against OI in HIV-infected African Children: The CHAP Trial. Abstract 706.
  19. Gasasira A, Kamya M, Achan J, et al. The Effect of Cotrimoxazole Prophylaxis and Insecticide-treated Bednets on the Risk of Malaria among HIV-infected Ugandan Children. Abstract 78.
  20. Theophil B, Kinabo G, Swai M. Positive Effect of Cotrimoxazole Prophylaxis in HIV-infected Children. Abstract 705.
  21. Noguera A, Alsina L, Muñoz-Almagro C, et al. Programmed Treatment Interruption in HIV-infected Children with Optimal Virological Response to First-line HAART: A 3-Year Follow-up. Abstract 723.
  22. Phillips U, Rosenberg M, Dobroszycki J, et al. Persistence of PI-resistance Mutations among Children Undergoing a PI-targeted Partial Treatment Interruption. Abstract 724.
  23. Compagnucci A, Saidi Y, Harper L, et al. Does Early Treatment Provide Long-term Benefit in HIV-1-infected Infants? 5-Year Outcomes in Children Treated before 3 Months of Age in the PENTA 7 Trial. Abstract 722.
  24. Mora S, Giacomet V, Zamproni I, et al. Alteration of Circulating Osteoimmune Factors May Be Responsible for Bone Metabolism Derangement in HIV-infected Children and Adolescents. Abstract 76.
  25. Chernoff MC, Nachman S, Williams P, et al. Psychotropic Drug Therapy and Psychiatric Symptoms in HIV-infected and -uninfected Children and Adolescents Enrolled in PACTG P1055. Abstract 709.
  26. Rutstein R, Josephs J, Gaur A, et al. Mental Health and Special Education Issues in a Cohort of HIV-infected Children: Results from a Multi-site Multi-state Survey of Caregivers. Abstract 710.
  27. Navarro M, Fontelos PM, Mellado M, et al. Chronic Hepatitis C Virus Infection in a Large Cohort of HIV-infected Spanish Children. Abstract 708.
  28. Dunn D, Woodburn P, Duong T, et al. A Comparison of the Association on Current CD4 Cell Count with Short-term Risk of AIDS of Death in HIV-infected Children and Adults. Abstract 700.

Table 1

Table 1: Significant Factors for Defining Appropriate Formula Feeding
DrugStudy NamePopulation/Inclusion CriteriaKey Findings
ATV with or without RTV boostingPACTG 1020A Phase I/II (n = 109) (a)
  • Age: 91 days to 21 years
  • ARV naive or experienced, but with phenosusceptibility to ATV
  • RNA >5,000 copies/mL
Acceptable safety profile and virological suppression with once daily ATV with or without RTV. RTV boosting needed for powder formulation.
LPV/RTV 300/75 mg/m2 twice daily + 2 NRTIsPACTG 1030 (n = 8) (b)
  • Age: <6 weeks
  • ARV naive
It was hypothesized that very young infants would need higher doses to achieve target exposure. A lower AUC was seen in these infants. The drugs were well tolerated. More research is needed.
LPV/RTV 400/100 mg/m2 twice daily with and without SQV or NNRTIPACTG 1038 (n = 26) (c)
  • Age: 2-18 years
  • PI experienced
In this pharmacokinetic study, it was concluded that a high dose can be safely used.
FPV alone or with RTV + 2 NRTIsAPV29005 (n = 75) (d)
  • Age: 2-18 years
  • ARV naive and experienced
Generally well tolerated with good antiviral activity (interim data).
FPV/RTV once dailyAPV2003 (n = 69) (e)
  • APV2003 (n = 69) (e)
Generally well tolerated with good antiviral activity (48-week data).
rC4-IG high-dose recombinant fusion protein CD4-IgG2 (PRO542)PACTG (n = 13) (f)
  • Age: 2-12 years
  • On stable ART for 3 months
  • HIV RNA ≥10,000 copies/mL
There is a nonlinearity in PRO542 pharmacokinetics in children (ie, no effect of a higher dose).
TPV/RTV oral solution or capsules; low and high dosesBI1182/PACTG1051 (n = 115) (g)
  • Age: 2-18 years
  • ARV naive and experienced
  • HIV RNA >1,500 copies/mL
40% of children on low dose and 46% on high dose had virological suppression (<400) at week 48. Genotypic inhibitory quotient (median TPV trough levels / number of TPV mutations at baseline) was strongest predictor of suppression.
Abbreviations:
ART = antiretroviral therapy
ARV = antiretroviral
ATZ = atazanavir
AUC = area under the curve
FPV = fosamprenavir
LPV = lopinavir
NNRTI = nonnucleoside reverse transcriptase inhibitor
NRTI = nucleoside reverse transcriptase inhibitor
PI = protease inhibitor
RTV = ritonavir
SQV = saquinavir
TPV = tipranavir


References:
a) Rutstein R, Samson P, Kiser J, et al. The PACTG 1020A Protocol: Atazanavir with or without Ritonavir in HIV-infected Infants, Children, and Adolescents. Abstract 715.
b) Pinto J, Robbins B, Chen J, et al. Pharmacokinetics and 24-Week Efficacy and Safety of Lopinavir/Ritonavir in HIV-1-infected Infants <6 Weeks of Age. Abstract 716.
c) Robbins B, Havens P, Capparelli E, et al. Pharmacokinetics of High-dose Lopinavir/Ritonavir with and without Saquinavir or NNRTI in HIV-infected Pediatric and Adolescent Patients Previously Treated with PI. Abstract 717.
d) Cunningham C, Freedman A, Read S, et al. Safety and Antiviral Activity of Fosamprenavir-containing Regimens in HIV-infected 2- to 18-Year-Old Pediatric Subjects (Interim Data, Study APV29005). Abstract 718.
e) Chadwick E, Borkowsky W, Fortuny C, et al. Safety and Antiviral Activity of Fosamprenavir/Ritonavir Once Daily Regimens in HIV-infected Pediatric Subjects Ages 2 to 18 Years (48-Week Interim Data, Study APV20003). Abstract 719.
f) Shearer W, DeVille J, Samson P, et al. Non-linear Pharmacokinetics of High-dose Recombinant Fusion Protein CD4-IgG2 Observed in HIV-1-infected Children. Abstract 721.
g) Salazar JC, Cahn P, Della Negra M, et al. Predictors of Response to TPV/r in Pediatric Patients: Results of PACTG1051/BI1182.14. Abstract 733.
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