Treatment Response, Mortality, and Adverse Events in Children with HIV

By Liz Highleyman

Despite the ability to prevent perinatal HIV transmission using antiretroviral drugs, children continue to become infected, especially in resource-limited countries.

While research on HIV in children lags behind adult research, several recent studies have looked at disease outcomes, treatment response, and adverse events in pediatric HIV patients.

Uganda vs U.K.

An MSF Doctor examines a young HIV-positive Ugands patient.

In the first study, described in the December 1, 2008 Journal of Acquired Immune Deficiency Syndromes, researchers compared responses to antiretroviral therapy (ART) among children and adolescents living in industrialized countries (the U.K. and Ireland) and a developing country (Uganda), looking at short-term immunological and virological responses as well as growth.

The investigators analyzed prospective cohort data from 582 children (age 4.4 to 11.6 years) at 54 U.K./Irish hospitals (the Collaborative HIV Paediatric Study) and 876 children (age 1.6 to 8.9 years) at Mulago Hospital in Kampala, Uganda. About three-quarters of the U.K./Irish children were black Africans, so differences in outcome could not be attributed to race/ethnicity.

The children initiated combination ART (at least 3 drugs from at least 2 different classes) and remained on treatment for at least 6 months. Participants were treatment-naive, but may have been exposed to antiretroviral drugs to prevent mother-to-child HIV transmission.

Responses were determined at 6 and 12 months after starting therapy. Predictors of viral load suppression < 400 copies/mL, CD4 percentage increases of greater than 10%, and height- and weight-for-age Z-score increases were analyzed using logistic regression.

Results

Overall, the U.K./Irish children were younger than the Ugandan children at the time of ART initiation (median 5.0 vs 7.6 years).

The U.K./Irish group also had a higher average CD4 percentage (14% vs 8%) and lower HIV viral load (172,491 vs 346,809 copies/mL) at baseline.

In addition, the U.K./Irish children showed less growth stunting (-0.8 vs -2.8) and less wasting (-0.6 and -2.8).

After ART initiation, median changes in viral load and CD4 percentage (+12% vs +13% at 12 months) were similar in the U.K./Irish and Ugandan groups.

Median weight gain (+0.4 vs +0.5) was also similar.

However, the Ugandan children achieved less growth (+0.20 vs +0.06 at 12 months; P < 0.001), and remained significantly shorter than the U.K./Irish children.

In both groups, older children were more likely to achieve viral suppression (P = 0.05), but younger children had better immunological response and weight and growth gains (P < 0.001).

Interestingly, lower pre-ART CD4 percentage predicted better immunological response in the U.K./Irish group, but poorer response in the Ugandan group.

Although 70% of children in both groups achieved HIV RNA < 400 copies/mL at 6 months, adolescents starting ART in the U.K./Ireland had somewhat poorer viral load responses than those in Uganda (P = 0.15).

Based on these findings, the study authors concluded, "Overall immunological and virologic ART responses were similar in children in both cohorts."

"Poorer CD4 recovery in more immunosuppressed Kampala children and blunted growth responses likely reflect higher background malnutrition and infection rates in Uganda," they added, "suggesting the need for earlier HIV diagnosis, nutritional support, cotrimoxazole prophylaxis, and ART."

Cotrimoxazole, or trimethoprim/sulfamethoxazole (Bactrim; Septra), is an antibiotic used as prophylaxis against various AIDS-related opportunistic infections (OIs). In the absence of such therapy, OIs likely contribute to poorer outcomes in Uganda.

Death and Loss to Follow-up

In the second study, reported in the December 2008 Journal of Acquired Immune Deficiency Syndromes, investigators with the KIDS-ART-LINC (Kids' Antiretroviral Treatment in Lower-Income Countries) Collaboration looked at outcomes among HIV-infected children starting ART in sub-Saharan Africa.

This pooled analysis included data from 2405 children (under age 15) at 16 participating clinics. Patients were about evenly divided between boys and girls and the median age was 4.9 years, with 12% being less than 1 year old. At the time of ART initiation, 70% had severe immunodeficiency, 53% had severe clinical illness, and 7% had severe anemia. More than half (59%) started with a non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, with most of the rest starting a protease inhibitor.

The researchers determined probabilities of death or loss to follow-up after ART initiation for the entire group, as well as factors predicting these outcomes in a subset of 1058 children with complete data available.

Results

A total of 153 children died during follow-up, for a 2-year risk of death after ART initiation of 6.9%.

A majority of deaths (74%) occurred within the first 6 months after starting treatment, including 57% within the first 3 months.

Just over 90% of deaths occurred within the first year of treatment, compared with just 9% during the second year.

Independent predictors of death were:

Severe anemia at baseline (adjusted hazard ratio [HR] 4.10);
Advanced immunodeficiency (adjusted HR 2.95);
Severe clinical status (adjusted HR 3.64.

187 children were lost to follow up, for a 2-year risk of 10.3%.

About 60% discontinued follow-up during the first year after starting ART.

Loss to follow-up was more likely in children with severe clinical status.

Risk of death or loss to follow-up did not differ based on age at ART initiation or type of regimen.

"Once on treatment, the 2-year risk of death is low but the [loss to follow-up] risk is substantial," the researchers concluded. "ART is still mainly initiated at advanced disease stage in African children, reinforcing the need for early HIV diagnosis, early initiation of ART, and procedures to increase program retention."

Immune Response

In a third study, published in the December 2008 issue of AIDS Research & Human Retroviruses, Spanish researchers looked at long-term immunological response and incidence of metabolic disorders in HIV-infected children on HAART.

This retrospective study included 55 children stratified into 3 groups according to pre-ART CD4 cell percentage and rate of immunological recovery:

CD4 < 5% at baseline and slow immunologic recovery
CD4 5%-15% at baseline and slow immunologic recovery
CD4 15% at baseline and rapid immunologic recovery (reference group).

Results

Overall, only 25% of children achieved adequate immune recovery after 8 years on HAART.

Children in the CD4 ? 5% group never achieved a mean CD4 percentage < 25% after 8 years of treatment.

All children experienced a significant increase in plasma cholesterol levels during the first 2 years of therapy.

After this point, cholesterol levels reached a plateau and remained stable through year 8 of follow-up.

A higher rate of lipodystrophy syndrome was observed in the reference group (100%), compared with the CD4 ? 5% group (47%) and the CD4 5%-15% group (65%) (P = 0.006).

Overall, the researchers concluded, having a low CD4 nadir (lowest-ever level) hindered immune reconstitution, while children with rapid immunological recovery showed a higher prevalence of lipodystrophy.

Antiretroviral Toxicities

Finally, a study reported in the December 1, 2008 Journal of Infectious Diseases looked at toxicities of antiretroviral drugs -- specifically nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) -- in the PACTG 219C trial.

The study included 2233 U.S. children at least 13 years of age who were perinatally infected with HIV and were receiving 2 or more NRTIs. The investigators evaluated the relative toxicities of the 5 most common NRTI pairs:

zidovudine (AZT; Retrovir) + lamivudine (3TC; Epivir)

zidovudine + didanosine (ddI; Videx)

stavudine (d4T; Zerit) + lamivudine

stavudine + didanosine

didanosine + lamivudine

Incidence rates for clinical and laboratory toxicities were estimated, and NRTI pairs were compared with regard to time to the first toxicity.

Results

The most common observed clinical toxicities were liver inflammation, peripheral neuropathy, lipodystrophy or lipoatrophy, and pancreatitis.

The most common laboratory toxicities were elevated anion gap (an indicator of mitochondrial toxicity), increased total amylase level, neutropenia (low white blood cell count), and thrombocytopenia (low platelet count).

The stavudine/lamivudine combination was associated with the highest combined incidence of clinical and laboratory toxicities, at 4.1%.

Zidovudine/didanosine was associated with the lowest combined toxicity incidence, at 1.9%.

Overall, combinations containing zidovudine were about half as likely to cause clinical toxicities as those containing stavudine (adjusted hazard ratio 0.49; P = .02).

Regimens containing didanosine were associated with a significantly lower rate of laboratory toxicities than those containing lamivudine (adjusted HR 0.78; P = .04).

The zidovudine/lamivudine backbone was associated with a lower rate of clinical toxicities than stavudine/didanosine or didanosine/lamivudine, but a higher rate of laboratory toxicities than zidovudine/didanosine.

Zidovudine/didanosine was associated with a lower rate of clinical toxicities than stavudine/lamivudine.

Based on these findings, the study authors concluded, "In children, regimens containing zidovudine have less toxicity than do those containing [stavudine], thereby supporting their use in first-line regimens."

Stavudine/lamivudine, stavudine/didanosine, and didanosine/lamivudine, they continued, "have similar toxicity rates and are appropriate for second-line therapy."

This study did not evaluate the newer NRTIs abacavir (Ziagen), emtricitabine (Emtriva), or tenofovir (Viread). Current U.S. federal guidelines recommend zidovudine or abacavir plus lamivudine or emtricitabine for first-line treatment of pediatric HIV patients. Stavudine/didanosine is not recommended due to adverse side effects.

1/13/09

References

A Kekitiinwa, KJ Lee, AS Walker, and others. Differences in Factors Associated With Initial Growth, CD4, and Viral Load Responses to ART in HIV-Infected Children in Kampala, Uganda, and the United Kingdom/Ireland. Journal of Acquired Immune Deficiency Syndromes 49(4): 384-392. December 1, 2008. (Abstract).

KIDS-ART-LINC Collaboration. Low Risk of Death, but Substantial Program Attrition, in Pediatric HIV Treatment Cohorts in Sub-Saharan Africa. Journal of Acquired Immune Deficiency Syndromes 49(5):523-531, December 2008. (Abstract).

S Resino, D Micheloud, B Larru, and others. Immunological Recovery and Metabolic Disorders in Severe Immunodeficiency HIV Type 1-Infected Children on Highly Active Antiretroviral Therapy. AIDS Research & Human Retroviruses 24(12): 1477-1484. December 2008. (Abstract).

RB Van Dyke, L Wang, PL Williams, and others (PACTG 219C team). Toxicities Associated with Dual Nucleoside Reverse-Transcriptase Inhibitor Regimens in HIV-Infected Children. Journal of Infectious Diseases 198(11): 1599-1608. December 1, 2008. (Abstract).