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Increasing Pediatric Diagnosis and Treatment: Implications of the 2008 WHO Pediatric HIV Treatment Recommendations

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HIV researchers and program managers in much of the world have experienced considerable angst regarding the slow development and implementation of strategies for the prevention and treatment of pediatric HIV infection. A series of recent advances in prevention and treatment has generated excitement, however, and it is important to examine these advances and to identify some challenges that have emerged. This article summarizes the major changes in the World Health Organization (WHO) pediatric guidelines published in April 2008, as well as the research behind them and the implications of the recommendations for infant diagnosis and infant and pediatric treatment in resource-limited settings.

Public health measures tend to be created in a compartmentalized fashion, which often presents challenges for attempts to integrate them into existing programs and to coordinate across potentially related programs. This has been evident in some international efforts targeting pediatric HIV infection. Initially, in resource-limited settings, the measures implemented for the prevention of mother-to-child-transmission (PMTCT) of HIV were simple. Use of short-term zidovudine (ZDV), single-dose nevirapine (sdNVP), and similar short courses of antiretroviral (ARV) medications reduces the risk of mother-to-child transmission roughly by half, from 25-30% to 10-15%. With extended treatment of mother or child during breast-feeding, transmission rates have been documented at 5-10% and below, as evidenced by the recent SWEN and PEPI-Malawi studies.( 1 , 2 )

Figure 1. Number of Children Receiving Antiretroviral Therapy in Low- and Middle-Income Countries, 2005-2007

Figure 1. Number of Children Under 15 Receiving Antiretroviral Therapy in low- and Middle-Income Countries, 2005-2007
Regional totals do not add up to the total for low- and middle-income countries because of rounding. Statistics are from Towards Universal Access: Scaling up HIV Services for Women and Children in the Health Sector - Progress Report 2008 . Image taken from the Children and AIDS: Third Stocktaking Report ( 16 , 17 ).

Considerable programmatic resources have been invested in PMTCT services at country and local levels, creating new infrastructure and implementation systems to increase uptake and penetration of these services. With the infusion of funds from donor programs such as the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria, large-scale efforts for the care and treatment of HIV-infected individuals are now being conceptualized and implemented. However, an estimated 370,000 infants and children were newly infected in 2007,( 3 ) and pediatric treatment coverage is reported by countries to be between <5% and 15%, indicating that implementation of prevention and treatment programs for children is far from comprehensive.

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When to Start Treatment

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Figure 2. Probability of Death or Severe Event under Deferred or Early Treatment

Figure 2. Probability of Death or other Severe Event
Panel A shows the probability of death. Panel B shows the probability of death or CDC stage C or severe B event.( 4 )

Treatment efforts for children have lagged behind implementation targeted at adults, despite encouraging signs of recent progress and developments. Results from the CHER trial, conducted in Johannesburg and Cape Town, South Africa, have galvanized interest in strategies for the treatment of infants.( 4 ) This multifaceted trial enrolled 377 recently diagnosed HIV-infected infants in the first 6-12 weeks of life. Those with normal CD4 percentages for age (=25%) were randomized to combination ARV therapy (ART) with ZDV, lamivudine (3TC), and lopinavir/ritonavir (LPV/r) (n = 252) vs deferred therapy with aggressive monitoring (n = 125). Infants in the deferred-treatment arm whose CD4 counts or percentages fell below 1,000 cells/µL or 20% were placed on therapy.

In June 2007, a Data Safety Monitoring Board (DSMB) performed a periodic review of the interim data from the CHER trial and determined that the treatment cohort was experiencing significantly better outcomes than the deferred group. Outcomes or endpoints were defined clinically (death or U.S. Centers for Disease Control and Prevention stage B/C events or toxicity) or immunologically (CD4 percentage <20%). With only 32 weeks of median follow-up, the study demonstrated a 75% reduction in mortality in the early-treatment arm compared with the deferred-treatment arm (Figure 2). The DSMB recommendations--to unblind the deferred arm of the study and to offer treatment to all infants in that portion of the trial--were rapidly implemented by the study team. The CHER study remains open and active as it continues to investigate whether infants receiving ART can successfully be taken off therapy at 12 or 24 months of age if their CD4 counts remain normal for age. Recent treatment interruption trials involving adults from both high- and low-resource settings have demonstrated inferior clinical outcomes with treatment interruption vs continuous therapy, and most experts consider this strategy for adults to be unwise.( 5 , 6 , 7 , 8 ) The pediatric medical community eagerly awaits results from the treatment interruption portion of CHER and related trials (iTHEMBA, BANA, PENTA 11).

The CHER trial results were published in the New England Journal of Medicine in November 2008.( 2 ) They previously had been presented at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in July 2007 and were reviewed by the WHO Pediatric Working Group later in 2007 and early in 2008, ultimately leading to new WHO pediatric HIV treatment recommendations released in April 2008.( 9 )

The major changes in the WHO recommendations were as follows:

transparent gif bullet A strong recommendation to treat all HIV-infected infants in the first year of life regardless of CD4 count or percentage (replacing previous recommendations that mandated treatment based on CD4 counts below an age-specific threshold, specifically below 1,500 cells/µL [25%])
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transparent gif bullet Associated with that, a strong recommendation for early diagnosis of infants born to HIV-infected women
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transparent gif bullet A provisional recommendation to consider the use of protease inhibitor (PI)-based ART for infants previously exposed to sdNVP
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Previous WHO recommendations mandated treatment for infants based on either of the following criteria:

transparent gif bullet CD4 percentage <20% if <18 months of age or <15% if =18 months of age (later amended to higher thresholds: CD4 percentage <25% if =11 months of age [CD4 count <1,500 cells/µL] and <20% if 12-35 months of age [CD4 count <750 cells/µL])
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transparent gif bullet History of AIDS-defining conditions or AIDS-defining opportunistic infections
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Figure 3. Correlation of CD4 Percentage and Death or Progression to AIDS, By Age Group

Figure 2. Distribution of Follow-Up and Events Within Age Groups, for Analyses of CD4 Percentage and Death and Progression to AIDS
Panel A shows the correlation between CD4 percentage and probability of death. Panel B shows the correlation between CD4 percentage and probability of progression to AIDS.( 10 )

The question of when to initiate ART for any newly diagnosed individual historically has been challenging and contentious. However, observational data demonstrate increasingly higher risks for rapid development of AIDS and death associated with decreasing age. This is best exemplified in the HPPMCS collaborative metaanalysis of natural history data from 3,941 subjects, derived from 8 cohort studies and 9 randomized trials conducted in the United States and Europe before the advent of effective combination therapy (Figure 3).( 10 ) In resource-limited countries, practical considerations resulted in CD4-guided decision making.

It was in this context and amid the uncertainty about "when to start" that the CHER study was initiated. Following publication of the CHER study's compelling results, the WHO reconsidered its position and released new recommendations to treat all HIV-infected infants <12 months of age regardless of CD4 count. Technically, CHER specifically addressed "when to start" for young infants <12 weeks of age--the population enrolled in the study. Deliberations by the WHO pediatric working group resulted in extension to 12 months, presumably based on the known high risk of adverse outcomes for untreated infants. Naturally, that raises the question of how the 12-month cutoff was determined. Infants who are slightly older also might benefit from treatment, and conversely, some infants who are <12 months of age, in good health, and tolerating infection successfully might continue to do well without therapy. Of course, the risk profile for infants is a continuum, with gradual decrease in risk with increasing age. Decision making is further complicated by the lack of effective predictive markers of disease progression for young infants. Clearly, additional data and continued assessment of optimal strategies are needed.

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Infant Diagnosis

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The new mandate to treat all infected infants who are <1 year of age highlights the urgent need for diagnostic capacity that is accurate and widely available. Because infants younger than 18-24 months of age have detectable, maternally acquired antibodies to HIV, the detection of HIV antigens is required for diagnosis. The preferred detection method is based on the polymerase chain reaction (PCR) technique: either detection of proviral DNA within cells (DNA PCR) or detection of viral RNA in blood plasma (RNA PCR). The recent advent of dried blood spots (DBS) as an acceptable source of testing material has simplified blood sampling, making comprehensive testing strategies feasible. Many countries have developed, or are in the process of developing, regional laboratories with sophisticated, high-throughput PCR capacity to which whole blood or DBS samples from infants can be sent for diagnosis. In the future, sensitive and specific field assays that can be performed in real time may be available; these are in development. The ability to coordinate across diverse health care facilities and diagnostic centers will be critical for successful diagnosis and treatment of infants: from prenatal clinics to PMTCT programs to laboratory diagnostic centers to pediatric treatment programs.

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What to Start

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The increasingly widespread use of sdNVP for PMTCT at the time of delivery for HIV-infected mothers and their newborns has underscored the question of what ARV regimen should be initiated when treatment criteria are met. Although the use of sdNVP has resulted in gratifying decreases of approximately 50% in perinatal HIV transmission, it has been associated with high levels of viral resistance to NVP both among the women who receive it and their infants who become HIV infected.( 11 ) As the vast majority of ARV regimens in resource-limited settings include nevirapine, a common concern is the increased risk of therapeutic failure on a regimen that contains a nonnucleoside reverse transcriptase inhibitor (NNRTI). Data from early experience in the PHPT-2 study and the Mashi study initially demonstrated inferior results with women on NNRTI-containing regimens following exposure to sdNVP.( 12 , 13 ) More recently, the A5208/OCTANE study, which compared NVP-based ART with LPV/r-based ART in women previously exposed to sdNVP, was halted early upon recommendation of the DSMB in October 2008 owing to inferior performance of the cohort treated with NVP.( 14 )

Key to Trials
Study Abbreviation Study Title Cohort Location
SWEN Six-Week Extended-Dose Nevirapine Study Ethiopia, India, Uganda
PEPI-Malawi Post-Exposure Prophylaxis of Infant (PEPI)-Malawi Study Malawi
CHER Children with HIV Early Antiretroviral Therapy Study South Africa
iTHEMBA iTHEMBA AIDS Foundation Study Sub-Saharan Africa
BANA Botswana/Baylor Antiretroviral Assessment Botswana
PENTA Paediatric European Network for Treatment of AIDS Study Multinational
HPPMCS HIV Paediatric Prognostic Markers Collaborative Study Europe, United States
PHPT-2 Perinatal HIV Prevention Trial-2 Thailand
Mashi Prevention of Milk-Borne Transmission of HIV-1C in Botswana ("Mashi") Study Botswana
A5208/OCTANE Optimal Combination Therapy After Nevirapine Exposure (OCTANE) Study Group Sub-Saharan Africa
IMPAACT P1060 International Maternal Pediatric Adolescent AIDS Clinical Trials P1060 India, Sub-Saharan Africa
NEVEREST Nevirapine Resistance Study South Africa
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At that time, Palumbo and Violari et al, who were conducting IMPAACT P1060, a study that was of similar design to A5208/OCTANE but targeting infants 6-36 months of age, carefully considered their position in consultation with the study's DSMB, the funding agency, and the internal review boards and ethics committees at the participating clinical trial sites. A consensus was reached to continue the trial as designed. During the third DSMB review in April 2009, detection of substantially better performance of the LPV/r treatment arm over that of the NVP arm among infants previously exposed to sdNVP prompted discontinuation of enrollment in Cohort I (sdNVP exposed), as the DSMB recommended. NVP-treated infants in Cohort I were evaluated with an option to switch to LPV/r-based therapy. By week 24 of the study, 40% of the NVP-exposed children in the NVP arm had either failed to adequately suppress HIV to undetectable levels or stopped taking their treatment regimen compared with 22% in the LPV/r treatment arm. When HIV replication control was examined, there was a 24% rate of failure to suppress the virus to undetectable levels in the NVP arm compared with a 7% failure rate in the LPV/r arm.( 15 ) IMPAACT P1060 and A5208/OCTANE are continuing to enroll participants into Cohort II (no previous sdNVP exposure), formally evaluating the relative performance of LPV/r- vs NVP-based regimens under these conditions.

The recent results of these two trials highlight the urgency of addressing the following central issues:

transparent gif bullet There is a need for next-generation strategies for PMTCT that are more effective than the use of sdNVP alone and that are protective from the emergence of NNRTI resistance. Top contenders are the use of ARV tails with sdNVP and expanded use of maternal ART.
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transparent gif bullet Innovative efforts are needed to increase access to PIs for first-line ART for infants exposed to sdNVP. History suggests that moving from concept to reality will be slow, but this should be prioritized at the WHO and on national levels.
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transparent gif bullet There are several concerns about second-line therapy options in resource-limited settings, including the potential role of newer ARVs such as additional PIs, etravirine, and raltegravir. In addition, it is unknown whether a sustainable cost basis can be established. Finally, the advisability of cycling back to NNRTIs after a period of PI use remains in question, although the awaited results from the NEVEREST trial may elucidate this issue.
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Sustainability

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Although some countries with limited resources have accepted and are implementing the new WHO pediatric treatment recommendations, many countries continue to consider and struggle with issues pertinent to their particular setting. Clearly there will be a substantial period of time between acknowledgement of evidence-based guidelines and widespread implementation. Most resource-limited countries are in a "roll out" mode, expanding health care infrastructure. Longstanding concerns regarding sustainability have become particularly cogent in light of the recent global financial crisis. Future funding resources were a major discussion point at the 15th International Conference on AIDS and STIs in Africa held in Dakar, Senegal, in December 2008. Several donor nations have already cut contributions to the Global Fund to Fight AIDS, TB, and Malaria. The U.S Congress approved $40 billion for renewal of the PEPFAR package and President Barack Obama has stated his position of strong support for HIV care and research efforts in the United States and internationally. However, these political positions and promises of financial support remain to be translated into policy and actual funding.

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Conclusion

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In order to take advantage of the recent exciting progress in our knowledge base and the momentum in health care implementation targeting prevention and treatment of pediatric HIV infection, all involved parties will need to exercise creativity and renewed commitment. Revisions of the WHO recommendations and other guidelines often lag behind new discoveries in prevention and treatment and can affect the willingness of national health ministries to move forward with enhanced methods for prevention and care. International organizations have a public health obligation to ensure that their guidelines are consistent with new evidence that can enhance HIV prevention and improve the health of those who are infected. Implementation of advances in pediatric prevention and treatment in resource-limited settings that are consistent with the "standard of care" remains a goal that must receive greater support from the public health community. In working toward this goal, it is essential to decrease structural barriers to pediatric diagnosis and treatment while increasing and clarifying preferred pediatric treatment options.

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References

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  1. Bedri A, Gudetta B, Isehak A, et al; Six Week Extended-Dose Nevirapine (SWEN) Study Team. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials . Lancet. 2008 Jul 26;372(9635):300-13.
  2. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission . N Engl J Med. 2008 Jul 10;359(2):119-29.
  3. Joint United Nations Programme on HIV/AIDS. 2008 Report on the Global AIDS Epidemic. Geneva: UNAIDS; 2008. p. 33. Available at: http://data.unaids.org/pub/GlobalReport/2008/JC1510_2008GlobalReport_en.zip
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  5. El-Sadr WM, Lundgren JD, Neaton JD, et al; Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment . N Engl J Med. N Engl J Med. 2006 Nov 30;355(22):2283-96.
  6. Danel C, Moh R, Minga A, et al; Trivacan ANRS 1269 Trial Group. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial . Lancet. 2006 Jun 17;367(9527):1981-9.
  7. Ananworanich J, Gayet-Ageron A, Le Braz M, et al; Staccato Study Group; Swiss HIV Cohort Study. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial . Lancet. 2006 Aug 5;368(9534):459-65.
  8. DART Trial Team. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts <200 cells/microl . AIDS. 2008 Jan 11;22(2):237-47.
  9. World Health Organization. WHO Pediatric Treatment Recommendations. Geneva: WHO; 2008. Available at: http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf
  10. Dunn D; HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis . Lancet. 2003 Nov 15;362(9396):1605-11.
  11. Eshleman SH, Krogstad P, Jackson JB, et al. Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377) . J Infect Dis. 2001 Jun 15;183(12):1732-8.
  12. Jourdain G, Ngo-Giang-Huong N, Tungyai P, et al; Perinatal HIV Prevention Trial Group. Exposure to intrapartum single-dose nevirapine and subsequent maternal 6-month response to NNRTI-based regimens. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 41LB.
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  14. Lockman S, A5208/OCTANE Study Team. Lopinavir/ritonavir + tenofovir/emtricitabine is superior to nevirapine + tenofovir/emtricitabine for women with prior exposure to single-dose nevirapine: A5208 ("OCTANE"). In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009. Abstract 94LB.
  15. National Institute of Allergy and Infectious Diseases, National Institutes of Health. Bulletin: Ritonavir-Boosted Lopinavir Proves Superior to Nevirapine in HIV-Infected Infants Who Received Single-Dose Nevirapine at Birth. Bethesda, MD: NIAID; May 6, 2009. Available at: http://www3.niaid.nih.gov/news/newsreleases/2009/P1060.htm
  16. Towards Universal Access: Scaling up HIV Services for Women and Children in the Health Sector: Progress Report, 2008. Geneva: UNAIDS, UNICEF, WHO; 2008. p. 33-34. Available at: http://www.unicef.org/aids/index_documents.html
  17. Children and AIDS: Third Stocktaking Report, 2008. Geneva: UNICEF; December 2008. p. 11. Available at: http://www.unicef.org/publications/index_46585.html
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