Use of antiretrovirals in HIV-infected children in a tuberculosis prevention trial: IMPAACT P1041.

SETTING: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1041, a tuberculosis (TB) prevention trial conducted among children enrolled from 2004 to 2008 during South Africa's roll-out of combination antiretroviral therapy (ART). OBJECTIVE: To estimate TB incidence and mortality and the effect of ART. DESIGN: Children were pre-screened to exclude TB disease and exposure, actively screened 3-monthly for TB exposure and symptoms, and provided post-exposure isoniazid prophylaxis therapy (IPT). TB diagnoses were definite, probable, or possible, and mortality all-cause. Testing was at the 5% significance level. RESULTS: In 539 children (aged 3-4 months) followed up for a median of 74 weeks (interquartile range [IQR] 48-116), incidence/100 person-years (py) was 10.67 (95%CI 8.47-13.26) for any TB and 2.89 (95%CI 1.85-4.31) for definite/probable TB. Any TB incidence was respectively 9.39, 13.59, and 9.83/100 py before, <180 days after, and 180 days after ART initiation. Adjusted analysis showed a non-significant increase in any TB (HR 1.32, 95%CI 0.71-2.52, P = 0.38) and a significant reduction in mortality (HR 0.39, 95%CI 0.17-0.82, P = 0.017) following ART initiation. CONCLUSIONS: ART reduced mortality but not TB incidence in human immunodeficiency virus (HIV) infected children in IMPAACT P1041, possibly attributable to active screening for TB exposure and symptoms with post-exposure IPT. Research into this as a strategy for TB prevention in high HIV-TB burden settings may be warranted.

Treatment interruption after pregnancy: effects on disease progression and laboratory findings.

OBJECTIVE: To assess clinical progression and inflammatory markers among women stopping or continuing antiretroviral therapy (ART) after pregnancy. METHODS: ART-naïve women with CD4+ lymphocyte counts >350 cells/uL initiating ART during pregnancy had clinical events and laboratory markers compared over one year postpartum between those stopping (n = 59) or continuing (n = 147) ART. RESULTS: Slopes in CD4 count and HIV RNA did not differ between groups overall and in subsets of ZDV or combination therapy. The hazard ratio (HR) of a new class B event was 2.09 (95% CI 0.79-5.58) among women stopping ART, 1.24 (0.31-4.95) in those stopping ZDV, and 2.93 (0.64-13.36) among those stopping combination therapy. Women stopping ART had increased immune activation. No significant differences were seen in C-reactive protein, lipids, leptin, or interleukin-6. CONCLUSIONS: While changes in CD4 and HIV RNA levels over one year were similar between women stopping or continuing ART postpartum, higher immune activation among women stopping therapy requires further study.

Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial.

Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and > or = 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach < 400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA < 400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.

Impact of GB virus type C infection on mother-to-child HIV transmission in the Women and Infants Transmission Study Cohort.

BACKGROUND: GB virus type C (GBV-C) viraemia is associated with a beneficial outcome in HIV-infected individuals in several though not all studies. GBV-C viraemia was examined in a matched case-control study of 133 HIV-infected pregnant women who transmitted HIV to their infants ('cases') and 266 non-transmitting controls. METHODS: HIV-infected children and controls were pair-matched for high-risk delivery, race and year of delivery. GBV-C status was determined in maternal plasma samples obtained at or within 3 months of delivery. RESULTS: Pregnant women with GBV-C viraemia (11% of those studied) had lower HIV RNA levels (P=0.01) and higher CD4 percentages (P=0.0006) [corrected] than women without GBV-C. A trend towards decreased mother-to-child transmission in the multivariate analysis was observed among GBV-C viraemic women delivering after highly active antiretroviral therapy (HAART) became available [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.08-1.05; P=0.06], but not in women delivering prior to the widespread use of HAART. CONCLUSIONS: GBV-C viraemia was associated with a beneficial effect on CD4 percentage and HIV RNA level in these pregnant women, and was also associated with a trend towards reduced risk of mother-to-child HIV transmission among women after HAART became available. Further studies with larger or multiple cohorts are necessary to assess possible benefits in this population.

Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings.

Cheaper, simpler alternatives to CD4 lymphocyte count and HIV-1 RNA detection for assessing the prognosis of HIV-1 infection are needed for resource-poor settings. However, little is known about the predictive value of alternative assays, in particular in children. We assessed the prognostic value of total lymphocyte count, immune complex-dissociated p24 antigen, white blood cell count, packed-cell volume (haematocrit), and serum albumin for mortality in 376 HIV-1-infected, mainly African-American or Hispanic children enrolled during March, 1988 to January, 1991. In a Cox proportional hazards model, including all assay-alternatives to CD4 and RNA, total lymphocyte count (p<0.0001) and serum albumin (p=0.0107) independently predicted mortality. Further assessment of these markers is warranted in resource-poor settings.

Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012).

OBJECTIVE: To examine the emergence and fading of NVP resistance (NVP(R)) mutations in HIV-1-infected Ugandan women and infants who received single dose NVP to prevent HIV-1 vertical transmission. DESIGN: We examined NVP(R) in women and infants who received NVP in the HIVNET 012 clinical trial, including 41 out of 48 women with infected infants, 70 randomly-selected women with uninfected infants, and 33 out of 49 infected infants. METHODS: Plasma HIV-1 was analyzed using the Applied Biosystems ViroSeq HIV-1 Genotyping System. RESULTS: NVP(R) mutations were detected in 21 out of 111 (19%) women tested 6-8 weeks after delivery. The rate of NVP(R) was similar among women whose infants were or were not HIV-1 infected. K103N was the most common mutation detected. NVP(R) mutations faded from detection within 12-24 months in all 11 evaluable women. High baseline viral load and low baseline CD4 cell count were associated with development of NVP(R). NVP(R) mutations were detected in 11 out of 24 (46%) evaluable infants who were infected by 6-8 weeks of age. The most common NVP(R) mutation detected in infants was Y181C. Those mutations faded from detection by 12 months of age in all seven evaluable infants. Of nine evaluable infants with late HIV-1 infection, only one had evidence of NVP(R). CONCLUSIONS: NVP(R) was detected more frequently in infants than women following NVP prophylaxis, and different patterns of NVP(R) mutations were detected in women versus infants. NVP(R) was detected infrequently in infants with late HIV-1 infection. NVP-resistant HIV-1 faded from detection in women and infants over time.

Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml.

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Patterns of plasma human immunodeficiency virus type 1 RNA response to highly active antiretroviral therapy in infected children.

This study examined the rate of decline in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels to <400 and <50 copies/mL in children receiving highly active antiretroviral therapy (HAART) consisting of efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors. Children receiving HAART achieved a plasma HIV-1 RNA level <400 copies/mL by a median of 4 weeks after initiation of therapy and a decline to <50 copies/mL by 20 weeks. Baseline plasma HIV-1 RNA levels affected the likelihood of achieving potent and sustained virus suppression, and children whose CD4 lymphocyte counts increased >70 cells/microL by 20 weeks on therapy were more likely to achieve durable virological and immunological benefit. These data provide time frames for virus suppression after the initiation of HAART that should be useful in evaluating the potential efficacy and durability of response of newly instituted combination antiretroviral therapy in HIV-1-infected children.

Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission.

OBJECTIVE: A recent trial in Uganda demonstrated that a simple, inexpensive regimen of nevirapine (NVP) prophylaxis can dramatically reduce HIV-1 vertical transmission risk. In this regimen, women receive a single dose of NVP at the onset of labor and infants receive a single dose of NVP within 72 h of birth. The objective of this study was to determine whether HIV-1 variants with NVP resistance mutations were selected in Ugandan women who received this regimen in the Phase I/II trial HIVNET 006. METHODS: Reverse transcriptase (RT) sequences from plasma HIV-1 were analyzed from 15 women 6 weeks after NVP dosing. RT sequences from plasma collected prior to NVP dosing were also analyzed. RESULTS: The K103N NVP resistance mutation was detected 6 weeks after NVP administration in three (20%) out of 15 women (95% confidence interval, 0-40%). Pre-dose samples were available from two of the three women; both pre-dose samples lacked the mutation. Other NVP resistance mutations were absent from all 15 women. Women with the K103N mutation had a longer median NVP elimination half-life, decreased median oral clearance, and increased median area under the concentration time curve than those without the mutation. An evaluable sample was obtained from one of these three women 33 months after delivery; the K103N mutation was not detected in that sample. CONCLUSIONS: This preliminary study demonstrates that HIV-1 with the RT K103N mutation can be detected in some Ugandan women following a single dose of NVP. This suggests that non-nucleoside RT inhibitor resistance may be selected in some people by single dose NVP prophylaxis. Pharmacokinetic data suggested that a more prolonged exposure to NVP after dosing may favor selection of NVP-resistant HIV-1.

Effects of negative life events on immune suppression in children and youth infected with human immunodeficiency virus type 1.

OBJECTIVES: To evaluate the association of negative stressful life events experienced over 12 months and the risk of moderate to severe immune suppression among children and youth infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Longitudinal study of 618 HIV-1-infected children, baseline ages 1 to 20 years (mean age: 6.4 years), who completed 52 weeks of participation in the Pediatric Late Outcomes Study (Pediatric AIDS Clinical Trials Group Protocol 219). Severity of immune suppression was indicated by the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System, based on CD4 percentages. The total number of negative life events-categorized as none, 1, or >1 life event reported as having occurred in the previous 12 months (previous 6 months for children <3 years of age)-was the predictor variable. Multiple logistic regressions were estimated to assess the relationship of negative life events and immune suppression at outcome, controlling for baseline measures of immune suppression, continuous CD4%, negative life events, age, race/ethnicity, gender, primary caretaker, education level of caretaker, and acquired immunodeficiency syndrome status. RESULTS: At week 52, 379 subjects (61% of total study population) had moderate to severe immune suppression. Of 275 children with normal immune function at baseline, 68 (24.7%) subsequently developed moderate to severe suppression levels by week 52 of follow-up. Of 343 children with immune suppression at baseline, 32 (9.2%) had recovered to normal CD4% levels by week 52. More than 1 negative life event was associated with an increased risk (prevalence) of immune suppression (odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.44,5.31), controlling for baseline CD4%, total life events, and other covariates. Children without immune suppression at baseline who experienced >1 negative life event had an increased incidence of immune suppression (OR: 2.93; 95% CI: 1.34,6.39), controlling for baseline covariates. CONCLUSIONS: Results indicate that negative stressful life events increase the risk of children with HIV-1 infection having impaired immune function. Further research is needed to identify potential mechanisms of the relationship between stressful life events and impaired immune function. These mechanisms include psychoneuroendocrinologic response and difficulties in adherence to therapy after exposure of a child to major negative life events.

Advances and research directions in the prevention of mother-to-child HIV-1 transmission.

Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and less-developed countries.

Quantification of human immunodeficiency virus type 1 p24 antigen and antibody rivals human immunodeficiency virus type 1 RNA and CD4+ enumeration for prognosis. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

BACKGROUND: The sensitivity, specificity and positive predictive value of baseline serum concentrations of HIV-1 immune complex-dissociated (ICD) p24 antigen for predicting disease progression and mortality were assessed and compared with results obtained for HIV-1 ICD p24 antigen with HIV-1 p24 antibody and for HIV-1 RNA with CD4+ lymphocyte percent. METHODS: Data from HIV-infected children enrolled in a North American clinical trial (National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial) were analyzed. Disease progression was defined as growth failure, CD4+ lymphocyte percent decline to <15% after study entry or development of an AIDS-defining opportunistic infection. RESULTS: Baseline samples were available for ICD p24 antigen testing (median concentration, 319 pg/ml; range, <50 to 15,640) in 240 children. The combination of detectable ICD p24 antigen and low p24 antibody was more sensitive but less specific than the combination of high HIV-1 RNA and low CD4+ lymphocyte percent in predicting disease progression and mortality. Using receiver operating characteristic curves, the specificity of ICD p24 antigen with p24 antibody for classifying children's disease progression or mortality was as great as, or greater than, HIV-1 RNA with CD4+ lymphocyte percent at points on the curve corresponding to higher sensitivity. CONCLUSIONS: The use of ICD p24 antigen with p24 antibody to identify children at high risk of disease progression or mortality could be a viable alternative to the more expensive and technically difficult HIV-1 RNA and CD4+ lymphocyte assays in resource-poor settings, including developing countries where the majority of children with HIV-1 infection reside.

Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273).

The clinical, immunologic, and virologic effects and the pharmacokinetics of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin (HIVIG) were assessed in 30 HIV-infected children aged 2-11 years. All had moderately advanced disease with an immune complex-dissociated (ICD) p24 antigen >70 pg/mL and were on stable antiviral therapy. Three groups of 10 children received 6 monthly infusions of 200, 400, or 800 mg/kg of HIVIG, and serial immunologic and virologic assays were performed. HIVIG doses as high as 800 mg/kg were safe and well tolerated. The half-life of HIVIG, determined by serial p24 antibody titers, was 13-16 days, the volume of distribution was 102-113 mL/kg, and clearance was 5.6-6.0 mL/kg/day. Plasma ICD p24 decreased during the infusions, but CD4 cell levels, plasma RNA copy number, cellular virus, immunoglobulin levels, and neutralizing antibody titers were minimally affected by the infusions. Clinical status did not change during the 6-month infusion and 3-month follow-up periods.

Technical report: perinatal human immunodeficiency virus testing and prevention of transmission. Committee on Pediatric Aids.

In 1994, the US Public Health Service published guidelines for the use of zidovudine to decrease the risk of perinatal transmission of human immunodeficiency virus (HIV). In 1995, the American Academy of Pediatrics and the US Public Health Service recommended documented, routine HIV education and testing with consent for all pregnant women in the United States. Widespread incorporation of these guidelines into clinical practice has resulted in a dramatic decrease in the rate of perinatal HIV transmission and has contributed to more than a 75% decrease in reported cases of pediatric acquired immunodeficiency syndrome (AIDS) since 1992. Substantial advances have been made in the treatment and monitoring of HIV infection; combination antiretroviral regimens that maximally suppress virus replication are now available. These regimens are recommended for pregnant and nonpregnant individuals who require treatment. Risk factors associated with perinatal HIV transmission are now better understood, and recent results from trials to decrease the rate of mother-to-child HIV transmission have contributed new strategies with established efficacy. However, perinatal HIV transmission still occurs; the Centers for Disease Control and Prevention estimates that 300 to 400 infected infants are born annually. Full implementation of recommendations for universal, routine prenatal HIV testing and evaluation of missed prevention opportunities will be critical to further decrease the incidence of pediatric HIV infection in the United States. This technical report summarizes recent advances in the prevention of perinatal transmission of HIV relevant to screening of pregnant women and their infants.

Maternal and infant factors predicting disease progression in human immunodeficiency virus type 1-infected infants. Women and Infants Transmission Study Group.

BACKGROUND: Infants with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection have widely variable courses. Previous studies showed that a number of maternal and infant factors, when analyzed separately, are associated with infant HIV-1 disease progression. In this study, clincal, virologic, and immunologic characteristics in the mothers and infants were examined together to determine the predictors of disease progression by 18 months of age and the associations with rapid progression during the first 6 months of life. METHODS: One hundred twenty-two HIV-1-infected women whose infants were HIV-1 infected were identified from the Women and Infants Transmission Study (WITS) cohort. WITS is a longitudinal natural history study of perinatal HIV-1 infection carried out in 6 sites in the continental United States and in Puerto Rico. The women were enrolled during pregnancy and their infants were enrolled at the time of delivery and followed prospectively by a standardized protocol. Virologic and immunologic studies were performed in laboratories certified by National Institutes of Health-sponsored quality assurance programs. Maternal factors in pregnancy were used as potential predictors of infant disease progression (progression to Centers for Disease Control and Prevention [CDC] Clinical Class C disease or death by 18 months of age) or as correlates of progression at <6 months of age. Infant factors defined during the first 6 months of life were used as potential predictors of progression during 6 to 18 months of age and as correlates of progression at <6 months of age. RESULTS: Progression by 18 months of age occurred in 32% of infants and by 6 months of age in 15%. Maternal characteristics that, by univariate analysis, were significant predictors of infant disease progression by 18 months of age were elevated viral load, depressed CD4(+)%, and depressed vitamin A. CD8(+)%, CD8(+) activation markers, zidovudine (ZDV) use, hard drug use, and gestational age at delivery were not. When examined in a combined multivariate analysis of maternal characteristics, only vitamin A concentration independently predicted infant progression. Infant characteristics during the first 6 months of life that, by univariate analysis, were associated with disease progression included elevated mean viral load at 1 to 6 months of age, depressed CD4(+)%, CDC Clinical Disease Category B, and growth delay. Early HIV-1 culture positivity (<48 hours), CD8(+)%, CD8(+) activation markers, and ZDV use during the first month of life did not predict progression. Multivariate analysis of infant characteristics showed that the only independent predictors were progression to CDC Category B by 6 months of age (odds ratio [OR], 5.80) and mean viral load from 1 to 6 months of age (OR, 1.99). The final combined maternal and infant analysis included the significant maternal and infant characteristics in a multivariate analysis. It showed that factors independently predicting infant progression by 18 months of age were progression to CDC Category B by 6 months of age (OR, 5.80) and elevated mean HIV-1 RNA copy number at 1 to 6 months of age (OR, 1.99). The characteristics associated with rapid progression to CDC Category C disease or death by 6 months of age were also examined. The only maternal characteristic associated with progression by 6 months in multivariate analysis was low maternal CD4(+)%. The infant characteristics associated with progression by 6 months of age in multivariate analysis were depressed mean CD4(+)% from birth through 2 months and the presence of lymphadenopathy, hepatomegaly, or splenomegaly by 3 months. Infant ZDV use was not assocciated with rapid progression. CONCLUSION: The strongest predictors of progression by 18 months are the presence of moderate clinical symptoms and elevated RNA copy number in the infants in the first 6 months of life. In contrast, progression by 6 months is associated with maternal and infant immun

Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team.

BACKGROUND: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.