Children and HIV

Antiretroviral Regimens for Young Children

Study Question: How safe and effective is aggressive HIV therapy for very young children? The combination therapies assessed in this study were {ZDV, 3TC, and NVP}; {ZDV, 3TC, NVP, and ABC}; and {D4T, 3TC, NVP, and NLF}.

Study Participants: The study analyzed data from the Pediatric AIDS Clinical Trial Group (PACTG) 356, a multi-center phase 1-2 trial. 52 Children (n=52) from the ages of 0.5 months to 24 months were enrolled. All the participants had received less than 10 weeks of prior therapy with nucleoside reverse-transcriptase inhibitors and none had ever received protease inhibitors.

Study Methods: Participants were sequentially enrolled in one of three treatment regimens. Children were treated for 200 weeks as long as their plasma HIV-1 RNA levels remained less than 1,000 copies per milliliter by 16 weeks. Physical examinations and complete blood counts were performed at study entry, every four weeks until week 24, every eight weeks until week 56, and every 12 weeks from week 56 to 200. Adverse events were recorded and graded. Children who enrolled and began antiretroviral therapy after the age of three months were considered to be in the delayed therapy group, while those who enrolled before the age of three months were considered in the early-therapy group.

Study Findings: For both groups, treatment associated adverse effects were infrequent. Viral replication was initially controlled in two children who began therapy at three months of age or earlier, but subsequently rebounded. Only one of the 52 children discontinued treatment because of adverse effects. Plasma HIV-1 RNA levels fell from a median of 5.3 log copies per milliliter (range 3.3 to 6.4 log copies per milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32 of the 52 infants. More children who received stavudine, lamivudine, nevirapine, and nelfinavir (D4T, 3TC, NVP, and NLF) had plasma levels of less than 400 copies per milliliter at 48 weeks and 200 weeks than children who received reverse transcriptase inhibitors alone. Fewer infants in the delayed therapy group than in the early-therapy group (30% vs. 60%) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 200 weeks.

Limitations: This study examined a relatively small sample. In addition, drug selection for infants was not randomized, but was determined sequentially. Larger randomized trials are required to conclusively define the optimal time to initiate therapy as well as optimal regimen for very young children.

Lessons Learned: This study provides evidence that three different regimens of antiretroviral therapy are safe, effective, and well tolerated for a four-year period when started in infancy. In addition, treatment at no more than three months with stavudine, lamivudine, nevaripanie, and nelfinavir is associated with improved long-term viral suppression. Providers should be aware of the efficacy and tolerability of these regimens in infants.

Source: Luzuriage, K., McManus, M., Mofenson, L., Britto, P., Graham, B., Sullivan, J.L., PACTG 356 Investigators. A trial of three antiretroviral regimens in HIV-1 infected children. New England Journal of Medicine, 2003, June 10; 350(24):2471-80.

Varicella Zoster and Immune Restoration Disease in HIV-infected Children

Study Question: Shortly after initiation of HAART, opportunistic infections are often exacerbated. This phenomenon has been termed Immune Restoration disease (IRD). What are the clinical and immune characteristics of Immune Restoration Disease (IRD) in HIV-infected children treated with HAART?

Study Participants: The study examined vertically HIV-infected children (n=61) who received their first stable HAART regimens from January 1996 through July 2002. The mean age of participants was 6.9 years +/- 4.7 standard deviation units. Two-thirds of the participants were girls, 56% of the participants were White, 38% were Black, and 7% were Hispanic.

Study Methods: This longitudinal study followed participants who were given standard prophylactic care based on guidelines for the treatment of HIV-infected children. Participants were examined at a minimum of three-month intervals. Each examination consisted of a thorough physical examination and blood tests to assess viral load, CD-4 count, as well as several indicators of metabolic functioning. Clinical outcomes in response to HAART were categorized. Immunologic success was defined as increase in CD4 cells greater than 5% or a total CD4 cell count greater than 250 cell/mL and viral success was defined as a decrease in plasma of greater than 2 log RNA or as achieving a plasma viral RNA load of less than 400 copies/mL.

Study Findings: In total, seven episodes of IRD occurred. All episodes of IRD were cutaneous herpes zoster (HZ). In all cases, the onset of HZ occurred within six months after the initiation of HAART. The average time of onset was 90 days after HAART initiation. Time of onset ranged from 36-198 days.. HZ occurred only in children with virological and immunological success to HAART. In addition, children who developed HZ had lower baseline CD4 and CD8 T-cell counts than children who did not develop HZ. Cases HZ were all mild and responded either to oral or intravenous acyclovir.

Limitations: The majority of sample was comprised of white girls, thus the characteristics of IRD described here may not apply across demographic characteristics. Several studies have shown that opportunistic infections decrease with HAART treatment and HZ is one of the most common childhood opportunistic infections. However, in this study, the incidence of HZ increased with HAART initiation. The conflict between these findings and related research suggests that further work is needed to clarify the relationship between HZ and HAART.

Lessons Learned: HZ is a common manifestation of IRD in HIV-infected children. The pathanogenesis of IRD is not well-understood, however vigorous immunologic and virologic responses to HAART are risk factors for developing HZ after HAART initiation. Providers should be aware that HZ in children can indicate successful immunologic and virologic reactions to HAART and will likely respond to oral or intravenous acyclovir.

Source: Tangsinmankong, N., Kamchaisatian, W., Lujan-Zilbermann, J., Brown, C., Sleasman, J., Emmanuel, P. Varicella zoster as a manifestation of immune restoration disease in HIV-infected children. Journal of Allergy and Clinical Immunology 113(4):742-6.

Unplanned Treatment Interruptions in Children on HAART

Study Question: How do unplanned interruptions in HAART treatment affect the CD4 levels of HIV-infected children?

Study Participants: N = 71 children. Most of the participants (67) were previously participants in UK and Ireland Collaborative HIV Pediatric Study (CHIPS). Four participants were receiving treatment at a hospital in the Netherlands. The majority (58%) of the participants were Black African. The report does not provide additional demographic information. The participants ranged in age from 0.7 years to 17.7 years. The median age was seven.

Study Methods: This study individually analyzed 82 of the 71 participants' treatment interruptions. (11 of the participants had two interruptions each.) CD4 Measurements obtained through the CHIPS study were used in this analysis. The rate of change in CD4 count and percentage during treatment interruptions was estimated using linear mixed models, allowing the slope to vary randomly between children.

Study Findings: Nearly one-half of the interruptions were described as due to "concerns about poor adherence". Nearly one-quarter of the interruptions were at the request of the parent or child. Nine percent of interruptions were caused by adverse drug reactions, and 21% resulted from a perceived lack of virologic or immunologic benefit. After 21% of the interruptions, the original HAART regimen was restarted and after 51% a new regimen was initiated. The average rate of CD4 decline during interruptions was 0.52% per month, which is similar to the rate of decline in adults, however, children showed significant variability. However, there was considerable variation in the rate of CD4 decline among individual children. In children re-initiated HAART, their median CD4 levels increased to pre-interruption levels by six months after re-initiation.

Limitations: This study does not identify factors that predict the rate of CD4 decline. In addition, because the decision to stop all ART is likely to be selective, interpretation of data obtained during treatment interruptions may be confounded by indicators for interruption. As a result pre-interruption signs of disease progression may be difficult to distinguish from the consequences of treatment interruption.

Lessons Learned: Providers should be aware that unplanned treatment interruptions have variable effects on the CD4 counts and percentages of HIV-infected children. In addition, it is important to note that, on average, CD4 counts and percentages return to pre-interruption levels in an average of six months after re-initiation of HAART.

Source: Gibb, D.M., Duong, T., Leclezio, V.A., Walker, A.S., Verweel, G., Dunn, D.T., Collaborative HIV Pediatric Study Steering Committee. Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection. Pediatric Infectious Disease Journal, 2004 May: 23(5):446-50.

Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir

Study Question: How does the integrity of mitochondria in HIV-1 uninfected infants born to HIV-1 infected mothers compare to the mitochondria of infants born to HIV-1 uninfected mothers?

Study Participants: Samples of cord blood and of the umbilical cord were obtained from HIV-1 uninfected infants born to 10 mothers with HIV infection who had taken Combivir and from infants of 9 uninfected mothers.

Study Methods: Mitochondrial morphological integrity was examined in umbilical cords (n=16) by electron microscope and mtDNA quantity was determined in DNA from cord blood (n=18) and umbilical cord by PCR-chemiluminescence immunoassay detection. The photomicrographs were coded and reviewed by the authors, research collaborators, and a panel of pathologists. Specialized tests were used to compare the quantity of mtDNA relative to nuclear DNA.

Study Findings: Mild to severe mitochondrial morphological damage was found in umbilical cords from six of nine Combivir-exposed infants. In contrast, six of seven unexposed infants showed no damage or minimal damage that was judged to be within normal limits. In the cord blood and umbilical cord samples, mtDNA depletion was statistically significant compared to unexposed infants. They did not find a relationship between the mother's viral load or clinical status and infant mitochondrial activity. They also examined other factors such as smoking, drug and alcohol use and did not find a correlation with mitochondrial damage. A strong correlation was found between the duration of Combivir exposure and the degree of mitochondrial damage.

Limitations: The sample size of this pilot study is small. The study compared uninfected infants born to HIV-infected mothers on Combivir to infants of mothers who did not have HIV. Thus, the infants born to mothers with HIV were exposed to both HIV and Combivir and either or both could be related to the mitochondrial dysfunction. A larger sample size and a greater variation in exposure to antiretroviral drugs are needed to answer the question more definitively.

Lessons Learned: The authors conclude that, taken together, the electron microscopy morphology and the mtDNA depletion data demonstrate that in many HIV-1 uninfected infants exposed in utero to Combivir, mitochondrial damage may be present at the molecular level, even in the absence of clinical effects. The correlation between duration of Combivir exposure and degree of mitochondrial damage provided evidence of a causal relationship. The authors note, however, that it is not possible to determine to what extent the observed mtDNA depletion may be due to the mother's HIV infection or to antiretroviral drug administration.

Source: Divi R.L., Walker V.E., Wade N.A., Nagashima K., Seilkop S.K., Adams M.E., Nesel C.J., O'Neill J.P., Abrams E.J., Poirier M.C. Mitochondrial damage and DNA depletion in cord blood and umbilical cord from infants exposed in utero to Combivir. AIDS. 2004 Apr 30;18(7):1013-21.

Lymphocyte Ratios and HIV-1 Intracellular DNA Levels in Children

Study Question: Is there an association between the CD4+:CD8+ ratio and the level of HIV-1 DNA in children with sustained undetectable RNA levels who had received combination antiretroviral therapy for more than 2 years?

Study Participants: 31 children ages 3 - 16 were also participants in PACTG 382 and were receiving combination ARV therapy. Children in this study had consistently undetectable HIV-1 RNA (viral load) for more than two years since they had been on HAART.

Study Methods: The study monitored a number of indicators of the children's immune systems and of HIV in the blood over a period of two years. These included CD4+ and CD8+ lymphocyte counts, the ratio of CD4+ to CD8+ cells, HIV-1 DNA levels, and HIV-1 RNA levels. The relationship between immune function and HIV-1 DNA levels was monitored over time.

Study Findings: HIV-1 DNA decreased gradually during the treatment with HAART and reached a plateau at week 104. There was no relationship between the CD4+:CD8+ ratio and the level of HIV DNA. Naïve CD4+ lymphocytes were the most common type of lymphocyte throughout the two-year study.

Limitations: The number of children in the study is small and all of them were on similar ARV regimens.

Lessons Learned: Studies in adults with HIV have found an inverse correlation between CD4+: CD8+ ratio and the level of HIV DNA in the blood. This study did not find that relationship even though the children had undetectable viral load and increasing CD4+ counts. The children had a greater percentage of naïve lymphocytes than memory lymphocytes-the opposite of what is found in adults. The study found that in children the CD4+:CD8+ ratio did not predict HIV-1 DNA levels probably because of the predominance of naïve lymphocytes. These data suggest that the increased proportion of naïve lymphocytes found in children are less susceptible to HIV-1 infection than are the memory lymphocytes found in adults when their CD4+ counts recover.

Source: Saitoh, A., Powell, C.A., Fenton, T., Douglas, S.D., Starr, S.E., Fletcher, C.V., & Spector, S.A. 2004. Longitudinal analysis of lymphocyte ratios and HIV-1 intracellular DNA levels in children. Journal of Infectious Diseases, 189, 1216-1220.

Pneumococcal Polysaccharide Vaccine in HIV-infected Children on HAART

Study Question: When children with HIV who are on HAART are given the pneumococcal vaccine, do they have an appropriate immune response and will they have clinical protection against pneumococcal disease?

Study Participants: The study population included 41 children (ages 2 to 15) with HIV infection who were receiving HAART therapy and 95 non-HIV infected children who had no evidence of immune dysfunction.

Study Methods: Blood level of antibodies (IgG) to specific pneumococcal types were measured before and after each child was vaccinated with 23-valent pneumococcal polysaccharide vaccine (23 PSV).

Study Findings: Both HIV-infected children and controls had low titers before the vaccination. After vaccination, both HIV-infected children and control children produced a significant increase in antibody titer. The average post-vaccination antibody titer was significantly lower in the HIV-infected subjects. The study also looked at clinical protection against pneumococcal disease before and after vaccination. Both groups developed higher clinical protection against invasive disease. Younger HIV-infected children (ages 2-6) had significantly lower clinical protection than the younger control group, but no difference in clinical protection was found in the older HIV group when compared with the older control group. Children with HIV whose CD4+ cell count was 25% or high developed more clinical protection that children with lower CD4+ counts. Children with HIV with a CD4+ count of >25% and a viral load less than 50 had the highest additional clinical protection gain.

Limitations: While the authors chose a conservatively high antibody level as a cutoff value for reliable immunologic protection, the specific antibody level of adequate protection is not known.

Lessons Learned: Children with HIV on HAART showed significant immune response to one dose of 23PSV (pneumococcal vaccine.) HIV-infected children with CD4+ cell counts greater than 25% at the time of vaccination developed better additional clinical protection gain than children with lower CD4+ counts. The highest benefit was seen in children with higher CD4+ counts and viral loads of less than 50 copies/mL whose clinical benefit resembled that of the control children. The authors note that considering the low cost and minimal adverse effects of 23PSV and the potential benefit of preventing invasive pneumococcal disease, this study provides strong support for the American Academy of Pediatrics recommendation for pneumococcal vaccination of children with HIV. They suggest giving 23PSV to HIV-infected children when CD4+ counts are high or revaccinating when CD4+ counts have increased with HAART.

Source: Tangsinmankong, N., Kamchaisatian, W., Day, N., Sleasman, J.W., Emmanuel, P. 2004. Immunogenicity of 23-valent pneumococcal poly saccharide vaccine in children with human immunodeficiency virus undergoing highly active antiretroviral therapy. Annals of Allergy, Asthma, and Immunology. 92, 558-564.