Newborn Hearing Screenings in Human Immunodeficiency Virus-Exposed Uninfected Infants.

Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.

Effect of HIV genotypic drug resistance testing on the management and clinical course of HIV-infected children and adolescents.

The clinical utility of genotypic drug resistance testing (DRT) in HIV-infected children on antiretroviral therapy (ART) is not well understood. HIV-infected patients aged <19 years undergoing DRT for virological failure were retrospectively enrolled. Indications for DRT and changes in HIV RNA load were recorded. Between January 2000 and December 2006, 57 patients had DRT. The most common indication for DRT was poor ART adherence (57.7% of patients). ART was changed in 50.9% of patients after DRT. Poor adherence was cited by clinicians for not changing ART significantly more often than any other reason (47.3%, P < 0.001). After DRT, significant improvement in HIV RNA load occurred independent of ART changes, though patients whose ART was modified were more likely to become undetectable (31.5% versus 7.0%, P < 0.001). Poor adherence was a significant factor for ordering DRT and for not changing ART in HIV-infected children.

Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030.

PURPOSE: To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia. METHODS: Subjects (N = 338) were HIV-infected with CD4+ count <100 cells/mm3, plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2). RESULTS: Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. During Step 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months. CONCLUSIONS: We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population.

Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics.

OBJECTIVES: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. METHODS: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). RESULTS: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90. CONCLUSIONS: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.

Poor outcome is associated with delayed tuberculosis diagnosis in HIV-infected children in Baja California, Mexico.

OBJECTIVE: To describe the morbidity and mortality associated with tuberculosis (TB) in human immunodeficiency virus (HIV) infected children in Baja California, Mexico. METHODS: Retrospective review of the medical records of all children with perinatally acquired HIV infection evaluated at Tijuana General Hospital with a diagnosis of TB between 1998 and 2007. The Stegen-Toledo (ST) clinical criteria for the diagnosis of TB were used. RESULTS: A total of 73 HIV-infected children were followed during the study period. Thirteen (18%) children were diagnosed with TB; one was confirmed by culture to be positive. Among these children, the mean ages at HIV and TB diagnosis were respectively 3.6 and 5.3 years. The mean ST score was 8.1; 10/13 had a score of >or=7, or highly probable TB. There were a cumulative 29 hospital admissions prior to TB diagnosis; 24 of these were due to pneumonia. The mean duration of symptoms at TB diagnosis was 73 days. The most common symptoms were cough (92%) and anorexia (85%). Seven patients (54%) had disseminated TB and five (39%) died as a consequence of TB. CONCLUSIONS: We observed high morbidity, hospital utilization and high mortality associated with TB among HIV-infected children in Baja California.

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.

Prevalence of primary HIV-1 drug resistance in pregnant women and in newly diagnosed adults at Tijuana General Hospital, Baja California, Mexico.

At Tijuana General Hospital, between March 2003 and June 2005, pregnant women and other adults, recently identified as HIV infected, antiretroviral naïve, were enrolled to examine the prevalence of primary HIV drug resistance. All subjects had the Calypte HIV-1 BED Incidence enzyme immunoassay test to identify recent infection. Genotypic analysis of HIV-1 protease and reverse transcriptase regions in plasma was performed. Forty-six subjects participated, eight (17%) men, 38 (83%) women. Ten (22%) subjects were classified as having recent HIV infection. HIV genotype was performed in 41 subjects. One subject (2.5%) had a major mutation in the reverse transcriptase region (K219Q) conferring zidovudine resistance, one had a minor mutation at V118I (2.5%) and two subjects (5%) had minor mutation (V179D) associated with non-nucleoside reverse transcriptase inhibitor resistance. There were no major protease inhibitor-associated mutations but minor mutations were common. The prevalence of primary HIV drug resistance in Baja California is low.

Performance of rapid HIV testing using Determine HIV-1/2 for the diagnosis of HIV infection during pregnancy in Tijuana, Baja California, Mexico.

The aim of this study was to evaluate the performance of the rapid antibody test Determine HIV-1/2, in pregnant women at Tijuana General Hospital. Pregnant women seeking prenatal care or admitted in labour had blood drawn for a rapid HIV test (Determine HIV-1/2), enzyme immunoassay (EIA) and Western blot. Between March and November 2003, 1068 women in labour and 1529 women in prenatal care were enrolled. The sensitivity, specificity, positive and negative predictive values were 100%, 99.8%, 77% and 100%, respectively. For women in labour, the mean time between blood collection and rapid test results was 92 minutes (range: 20-205 minutes) compared with 41 hours (range 24-120 hours) for HIV EIA (P = 0.012). All HIV-exposed infants received oral zidovudine. These findings indicate that the rapid test Determine HIV-1/2 has a high sensitivity and specificity in pregnant women. Rapid HIV testing greatly diminishes the time to diagnosis and enables prompt intervention with antiretrovirals at delivery.

The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy.

BACKGROUND: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). METHOD: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. RESULTS: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. CONCLUSION: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Human immunodeficiency virus type 1 (HIV-1) gp120-specific antibodies in neonates receiving an HIV-1 recombinant gp120 vaccine.

Infants born to human immunodeficiency virus type 1 (HIV-1)-infected mothers were immunized at birth and at ages 4, 12, and 20 weeks with low-, medium-, or high-dose recombinant gp120 vaccine with MF59 adjuvant (HIV-1(SF-2); n=52) or with MF59 alone as a placebo (n=9). An accelerated schedule (birth and ages 2, 8, and 20 weeks) was used for an additional 10 infants receiving the defined optimal dose and for 3 infants receiving placebo. At 24 weeks, anti-gp120 ELISA titers were greater for vaccine-immunized than for placebo-immunized infants on both schedules, and 87% of vaccinees had a vaccine-induced antibody response. At 12 weeks, antibody titers of infants on the accelerated vaccine schedule exceeded those of infants receiving placebo (4949 vs. 551; P=.01), and 63% of the vaccinees met the response criteria. Thus, an accelerated schedule of gp120 vaccinations generated an antibody response to HIV-1 envelope distinct from transplacental maternal antibody by age 12 weeks. These results provide support for further studies of vaccine strategies to prevent mother-to-infant HIV-1 transmission.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

Comparison of quantitative and qualitative PCR assays for cytomegalovirus DNA in plasma.

We analyzed the performance characteristics of the qualitative AMPLICOR CMV Test (Roche Molecular Systems, Pleasanton, Calif.) and quantitative COBAS AMPLICOR CMV MONITOR Test (Roche Molecular Systems) assays and compared the performance of the AMPLICOR quantitative assay with an in-house-developed cytomegalovirus (CMV) DNA PCR assay. The quantitative AMPLICOR assay was found to be more sensitive than the qualitative AMPLICOR assay. The quantitative AMPLICOR assay has a lower limit of sensitivity of 400 CMV DNA copies/ml of plasma and is linear to 50,000 CMV DNA copies/ml of plasma. Compared to the in-house PCR assay, the AMPLICOR quantitative assay gave lower viral load values at all concentrations tested, but the difference between the two assays was not consistent across the entire dynamic range of the AMPLICOR quantitative assay. At the lower end of the assay, the viral load values obtained with the in-house PCR assay were three- to fivefold (0.5 to 0.7 log units) higher than those measured with the AMPLICOR assay. At higher input concentrations, the differences between the two assays approached 10-fold. This direct comparison of the in-house assay and the quantitative AMPLICOR assay provides the ability to compare previously published in-house data with an assay widely available for future research and clinical monitoring of patients with CMV infections.

Impaired hepatocyte glucose transport protein (GLUT2) internalization in chronic pancreatitis.

Chronic pancreatitis (CP) is associated with impaired glucose tolerance and with reduced hepatic sensitivity to insulin. We have previously shown that in normal and sham-operated rats, insulin suppresses hepatic glucose production, and this suppression is associated with a decrease in the hepatocyte plasma membrane-bound quantity of the facilitative glucose transport protein GLUT2. The insulin-mediated reduction in membrane-bound GLUT2 is impaired in CP, and may play a role in the glucose intolerance associated with CP. To determine whether GLUT2 is actively internalized and whether this mechanism is disordered in CP, livers from fed and fasting rats in whom CP had been induced 2-3 months earlier by pancreatic duct oleic acid infusion, and in sham-operated (sham) rats, were fractionated to yield endosome (E)- and plasma membrane (PM)-enriched fractions. Forty-five minutes after duodenal intubation alone (fasting) or intubation plus duodenal feeding, livers were removed, homogenized and ultracentrifuged, and microsomal pellets were separated by sucrose density gradient ultracentrifugation. GLUT2 content of fractions was determined by Western blotting and scanning densitometry. The E:PM ratio of GLUT2 increased from 0.68 +/- 0.11 (mean +/- SEM) in fasting sham livers (n = 8) to 1.04 +/- 0.09 in fed sham livers (n = 8; p < 0.05). However, there was no change in the E:PM ratio of GLUT2 in CP livers after duodenal feeding (0.90 +/- 0.12 vs. 0.86 +/- 0.10; n = 8,8; p = NS). To test our findings using confocal laser scanning microscopy, liver specimens from fed and fasting CP and sham rats were minced, fixed in 4% paraformaldehyde, sectioned, and stained with rabbit antirat GLUT2 antibody followed by rhodamine-labeled secondary antibody. GLUT2 was quantified by mean pixel intensity in an 8 x 16-pixel area of PM and a 16 x 16-pixel area of cytosol (CYT) in each of 30 random cells/field (400x) in each of three rats per group. As in the fractionation study, duodenal feeding increased the CYT:PM ratio of GLUT2 from 0.75 +/- 0.01 in fasting sham liver to 0.86 +/- 0.01 in fed sham liver (p < 0.0001), while the CYT:PM ratio in CP remained unchanged. We conclude that feeding induces a shift in GLUT2 from the plasma membrane to the endosomal pool. The feeding-induced internalization of GLUT2 is absent in livers from rats with CP and may play a role in the glucose intolerance associated with CP.

Factors impacting on drug choices. Issues for developing countries.

In considering factors that impact on drug choices for children in developing countries, it is important to learn from the advances in antiretroviral therapy that have been made in the United States and other developed countries. Abundant clinical data indicate that monotherapy with antiretroviral agents, no matter how potent, is inadequate and the children should be treated with three or more drugs. When treatment regimens are changed, at least two new drugs should be started simultaneouly to avoid the rapid development of resistance. Understanding the impact of host and viral genotypes may provide information as to how best to treat the individual child. However, at present, I believe that with limited resources, the best use of antiretrovirals for children is in disease prevention. Thus, antiretrovirals to prevent mother-to-infant transmission should be given the highest priority. Second, children in the first year of life are at highest risk of progression and should be treated with trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonia, and targeted for receiving antiretrovirals. Moreover, treating children without an overall plan is unacceptable. Treatment with drugs because they are available will have little impact on the quality of life or disease progression unless they are used in combination. There should be no reason for children, no matter where they might live, to receive suboptimal antiretroviral therapy. For this reason, I call upon industrialized countries and the World Bank to help provide resources for the care and treatment of HIV-infected children. Additionally, I would propose that pharmaceutical companies provide support for the care and treatment of HIV-infected children. The drugs and financial support provided by pharmaceutical companies should go to a central foundation or group that will optimize the use of these resources for children in developing countries. I would also propose that in the United States, Europe, and other industrialized countries the patents on antiretroviral drugs be extended according to a formula based on the donation of a pharmaceutical company. It is only through a unified effort that we will be able to adequately treat all children infected with HIV regardless of where they might live.

Oral ganciclovir in children: pharmacokinetics, safety, tolerance, and antiviral effects. The Pediatric AIDS Clinical Trials Group.

The pharmacokinetics, safety, tolerance, and antiviral effects of ganciclovir (Gcv) administered orally were evaluated in 36 children infected with cytomegalovirus (CMV) who were severely immunocompromised by infection with human immunodeficiency virus type 1. In this dose-escalation study, 30 mg/kg of Gcv administered every 8 h produced serum levels similar to the dose (1 g/8 h) effective for maintenance treatment of CMV retinitis in adults. In older children, serum Gcv concentrations were similar after the administration of capsules and suspension. All doses (10-50 mg/kg/8 h) studied were safe and, except for the volume of suspension or number of pills, were well tolerated. Oral Gcv was associated with a decrease in the detection of CMV by culture or polymerase chain reaction. CMV disease occurred in 3 children during the study: one developed Gcv resistance, another had harbored resistant virus at study entry, and a third had wild-type CMV

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.