Antiretroviral resistance in viral isolates from HIV-1-transmitting mothers and their infants.

OBJECTIVE: To characterize concordance of resistance mutations to antiretroviral drugs (ART) in mother-infant pairs. DESIGN: Case series of HIV-transmitting mothers and infants in the Women and Infants Transmission Study, where delivery occurred between April 1994 and December 1999. METHODS: Reverse transcriptase and protease genes were sequenced in stored viral isolates from 32 mother-infant pairs. Mutations were coded as "pure mutants" where only mutant virus was detected or as "mixtures" where a mixed mutant/wild-type population was identified. ART resistance mutations were compared for concordance between mothers and their infants. RESULTS: Maternal mutations associated with resistance to nucleoside reverse transcriptase inhibitor (NRTI) and minor protease inhibitor (PI) drugs were typically concordant with that of infant, while those associated with non-nucleoside reverse transcriptase inhibitors (NNRTI) and major PI drugs were not. Of five NRTI-associated maternal mutations observed, three pure mutants corresponded with mutant in the infant, while two wild-type-predominant mixtures corresponded with infant wild type. The only NNRTI-associated mutation observed, K103N, was not transmitted, nor were the two major PI-associated mutations, L90M and V82I/V. Transmission of minor PI-associated mutations was consistent with the sole observed or dominant variant for 20 of 21 mutations. CONCLUSIONS: For NRTI- and minor PI-associated mutations, transmission was consistent with relative quantity of variants in maternal virus. However, where NNRTI- and major PI-associated mutations were present in three cases, they were not transmitted, even where only mutant virus was detectable in maternal isolates. This is consistent with evidence of loss of transmission with resistance to NNRTI and PI drugs.

Hepatitis C virus coinfection and HIV load, CD4+ cell percentage, and clinical progression to AIDS or death among HIV-infected women: Women and Infants Transmission Study.

BACKGROUND: Despite previous study, it remains unclear whether hepatitis C virus (HCV) coinfection affects the progression of human immunodeficiency virus (HIV) type 1 infection. The Women and Infants Transmission Study provided an opportunity to assess this issue. METHODS: Longitudinal data on 652 HIV-1-infected women enrolled in the study before the availability of highly active antiretroviral therapy (HAART; 1989-1995) were analyzed. Random effects models were used to determine whether HCV coinfection was associated with different CD4+ cell percentages and HIV-1 RNA levels over time, and Cox proportional hazards models were used to compare the rates of clinical progression to acquired immunodeficiency syndrome (AIDS) or death. RESULTS: Of 652 women, 190 (29%) were HCV infected. During follow-up, 19% of women were exposed to HAART. After controlling for indicators of disease progression (CD4+ cell percentages and HIV-1 RNA levels determined closest to the time of delivery in pregnant women), ongoing drug use, receipt of antiretroviral therapy, and other important covariates, no differences were detected in the HIV-1 RNA levels, but the CD4+ cell percentages were slightly higher in HCV-infected women than in HCV-uninfected women. During follow-up, 48 women had progression to a first clinical AIDS-defining illness (ADI), and 26 died with no documented antecedent ADI. In multivariable analyses, HCV-infected participants did not have faster progression to a first class C AIDS-defining event or death (relative hazard, 0.75; 95% confidence interval, 0.37-1.53). CONCLUSIONS: In this cohort, the rate of clinical progression of HIV-1 infection was not greater for HCV-infected women.

Gag-p6 Tsg101 binding site duplications in maternal-infant HIV infection.

Prevalence and patterns of HIV p6 duplications in HIV-1 mother-to-baby transmission are examined. Resistance genotyping was performed in a multisite U.S. study of antiretroviral resistance in vertical transmission. Sequence data were used in secondary analyses of HIV genetic variation. Two hundred sixty HIV viral RNA samples from HIV-infected pregnant women and their infants were analyzed with a commercial resistance genotyping kit. Chromatograms were examined for variability in the 3' region of gag. From 103 mother-baby sets, 190 samples gave readable p6 sequence. Of 103 mother-baby sets, 20 (19%) showed duplication of between 3 and 12 codons ending at the PTAPP motif of p6. When maternal p6 duplication was present and the p6 sequence was available from both maternal and infant isolates, all (seven of seven) infants had p6 duplications, but two cases showed discordancies between maternal and infant sequences. The prevalence of p6 duplication varied among geographical sites, ranging from 4 of 43 families (9%, Puerto Rico and New York sites) to 16 of 60 families (27%, Massachusetts, Texas, and Illinois). The presence of p6 duplication was not associated with differences in transmission, viral load, or disease progression in the infants, but showed a trend toward association with lower maternal CD4 count. Substantial p6 variation data are generated by resistance genotyping. PTAP duplication is prevalent in this group of HIV-infected women and infants. The duplication is efficiently transmitted from mother to infant, is present at variable prevalence at different geographic sites, and shows no clear association with vertical transmission risks.

Morbidity and mortality during the first two years of life among uninfected children born to human immunodeficiency virus type 1-infected women: the women and infants transmission study.

OBJECTIVE: We evaluated morbidity and mortality during the first 2 years of life among children born to human immunodeficiency virus-(HIV) type 1-infected women enrolled in the Women and Infants Transmission Study (WITS) during an 11-year period (1990-2001). DESIGN AND METHODS: As part of WITS, evaluations were performed at birth and at 1, 2, 4, 6, 9, 12, 18 and 24 months of age. Growth, hospitalization and the incidence of clinical disease were assessed regularly. RESULTS: Data regarding 1118 children born to HIV-infected women (955 HIV-uninfected children and 163 HIV-infected children) were analyzed. Fewer changes in the caretaker of the child and fewer in utero exposures to drugs, tobacco and alcohol occurred in the latter periods of the study (all P values for time trend analyses <0.01). The percentages of HIV-uninfected children with poor weight gain (44 of 767; 5.7%), short stature (32 of 703; 4.5%) and wasting (27 of 792; 3.4%) were higher than expected for the general population. Two or more changes in caretaker were associated with all growth deficiencies except wasting, and fetal exposure to tobacco was associated with height abnormalities. Anemia was common and was associated with receipt of zidovudine prophylaxis. Morbidity and mortality decreased during the study period. For the uninfected children, a decrease in class A events (Kaplan-Meier rates: group 1, 22.3%; group 2, 6.8%; group 3, 4.2%; P < 0.001) and class C events and death (Kaplan- Meier event rates: group 1, 2.0%; group 2, 1.7%; group 3, 0.2%; P = 0.062) during the first 2 years of life account for the differences in the curves over time. CONCLUSIONS: During an 11-year period, morbidity and mortality during the first 24 months of life decreased substantially for children born to HIV-infected women.

Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudine in the first three months of life.

BACKGROUND: There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HIV)-infected women. METHODS: Pharmacokinetics and tolerance of didanosine (ddI) were determined for infants < or =120 days of age. Infants received at least 24 hours of zidovudine (ZDV) treatment, followed by a single ddI dose and pharmacokinetic sampling. The target area under the concentration-time curve (AUC) was between 2.5 and 5.0 microM . hour. Toxicity and drug resistance mutations were assessed at baseline and follow-up times. RESULTS: The initial ddI pharmacokinetic dosing of 50 mg/m for infants >28 days of age achieved a median AUC0-infinity of 2.8 microM . hour. For infants < or =28 days of age, the target AUC was achieved after dose escalation from 25 mg/m (median AUC0-infinity, 1.4 microM . hour) to 50 mg/m (median AUC0-infinity, 5.40 microM . hour). At baseline, 25% of infected infants had drug resistance mutations (9 of 44 to ZDV and 2 of 44 to ddI). Resistance mutations were present for 29% of infants (5 of 17 infants) with in utero ZDV exposure and 25% (8 of 32 infants) with prior ZDV treatment. The most common ZDV mutation noted at baseline was the T215Y/F (n = 7) mutation; 2 of these infants also had the M41L mutation, which is associated with high level ZDV resistance. No prior exposure was noted for the 2 infants with ddI resistance, which indicates possible perinatal transmission of ddI-resistant virus to these infants. CONCLUSIONS: A dose of 50 mg/m is the appropriate ddI dose for infants <120 days of age and is a safe treatment for newborns when used in combination with ZDV. Genotypic resistance occurs frequently among infected infants exposed to ZDV during gestation or postnatally, which suggests that resistance testing should be considered for infants with newly diagnosed HIV infection.

Phase I/II trial of intravenous recombinant interleukin-2 in HIV-infected children.

OBJECTIVES: To define the tolerated dose of recombinant interleukin-2 (rIL-2) in HIV-infected children (part A), and to determine the safety and immunologic effects of the tolerated rIL-2 dose in a cohort of HIV-infected children (part B). DESIGN: Open-label, dose-escalation. SETTING: Multiple center study. SUBJECTS: Twenty HIV-infected children, aged 3-12 years. INTERVENTION: In part A six subjects received 1 x 10(6) IU/m2 and four subjects received 4 x 10(6) IU/m2 rIL-2 by continuous intravenous infusion for 5 days every 8 weeks for three cycles. In part B 10 different subjects received 1 x 10(6) IU/m2 for 5 days every 8 weeks for six cycles. MAIN OUTCOME MEASURES: Toxicity, CD4 cell count and percentage, and viral load. RESULTS: The tolerated dose of rIL-2 was 1 x 10(6) IU/m2. The most common side effects were fever and vomiting. Of 10 subjects enrolled in part B of the study, five discontinued rIL-2 therapy for a variety of reasons, most related to administration of study drug. Comparable rises in CD4 cell count and percentage were observed in each of the treatment arms. Six cycles of rIL-2 therapy did not appear to be better than three cycles with respect to improvement of CD4 parameters. Transient rises in plasma HIV-1 RNA levels were detected in some subjects. CONCLUSIONS: These results suggest that rIL-2 therapy can raise CD4 cell counts and percentages in some HIV-infected children, although a high proportion of HIV-infected children may have to discontinue intravenous therapy because of drug- or administration-related toxicity. Controlled trials of rIL-2 in this patient population are warranted.

Risk factors for Kaposi's sarcoma-associated herpesvirus infection among HIV-1-infected pregnant women in the USA.

OBJECTIVES: We sought to identify risk factors for infection with the Kaposi's Sarcoma-associated herpesvirus (KSHV) among pregnant women and to examine a reported association of KSHV with injecting drug use (IDU) and hepatitis C virus (HCV) infection. DESIGN: Cross-sectional evaluation of questionnaire data and KSHV and HCV seroprevalence in the Women and Infants Transmission Study. METHODS: In sera collected from HIV-1-infected pregnant women (n = 887) and, at age 12 months, their offspring (n = 900) at six sites in the USA and Puerto Rico, KSHV and HCV antibodies were detected with sensitive and specific enzyme immunoassays. Risk of KSHV was estimated by the unadjusted and adjusted odds ratio (OR(adj)) and 95% confidence interval (CI). The geographic referent sites were Chicago and Boston. RESULTS: Forty-seven (5.3%) of the women and three (0.3%) of the infants were KSHV seropositive. In univariate and multivariate analyses, KSHV in the women was associated with enrollment in Puerto Rico, Houston or Brooklyn (OR(adj), 4.3; 95% CI, 1.8-10.4) or Manhattan (OR(adj), 9.8; 95% CI, 3.7-25.6); non-completion of high school (OR(adj), 1.8; 95% CI, 0.9-3.4); the number of sexually transmitted diseases (OR(adj), 1.4; 95% CI, 1.0-1.9 per disease); and especially with IDU and HCV infection (OR(adj), 3.5; 95% CI, 1.5-7.9). CONCLUSIONS: Transmission of KSHV by blood inoculation may be highly inefficient, but our data support the hypothesis that it does occur. Large formal studies to evaluate whether KSHV transmission occurs via transfusion are needed to inform decisions regarding screening volunteer blood donors to protect the blood supply.

Time trends for HIV-1 antiretroviral resistance among antiretroviral-experienced and naive pregnant women in New York City during 1991 to early 2001.

Time trends in the prevalence of drug resistance to antiretroviral therapy (ART) in pregnant women have not been studied. Treatment and prophylactic efficacy could be compromised by drug-resistant HIV strains. We conducted a repeated cross-sectional study of antiretroviral resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and of major mutations to protease inhibitors (PIs) in virus isolates from 300 HIV-infected pregnant women in New York City from 1991 to early 2001. The overall prevalence of mutations for NRTIs from 1991 to early 2001 was higher for ART-experienced (25.6% [95% confidence interval (CI): 19.1% to 32.1%]) than ART-naive (8.6% [95% CI: 3.7% to 13.4%]) mothers (P < 0.002). For NNRTIs, the overall prevalence of mutations was somewhat higher among ART-experienced (5.8% [95% CI: 2.3% to 9.3%]) versus ART-naive (1.6% [95% CI: 0% to 3.7%]) women (P = 0.06), and increased over time for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-19.4%; P = 0.0002). The prevalence of PI-associated mutations was also higher overall among ART-experienced mothers (5.8% [95% CI: 2.3% to 9.3%] vs. 1.6% [95% CI: 0% to 3.7%]; P = 0.06), with increases over time seen for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-16.1%; P = 0.0008). The increasing prevalence of drug resistance in pregnant women, including those who are drug-naive, underscores the necessity for resistance testing to guide treatment to achieve suppression of the mother's virus.

Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy.

Data from 2543 HIV-infected women were analyzed to correlate antiretroviral therapy (ART) used during pregnancy with maternal and pregnancy outcomes. ART was analyzed according to class of agents used and according to monotherapy versus combination ART containing neither protease inhibitors (PIs) nor nonnucleoside reverse transcriptase inhibitors versus highly active ART. Timing of ART was classified according to early (recorded at or before 25-week gestation study visit) and late (recorded at 32-week gestation or delivery visit) use. Maternal outcomes assessed included hematologic, gastrointestinal, neurologic, renal, and dermatologic complications; gestational diabetes; lactic acidosis; and death. Adverse pregnancy outcomes assessed included hypertensive complications; pre-term labor or rupture of membranes; preterm delivery (PTD); low birth weight; and stillbirth. Logistic regression analyses controlling for multiple covariates revealed ART to be independently associated with few maternal complications: ART use was associated with anemia (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.1-2.4), and late use of ART was associated with gestational diabetes (OR = 3.5, 95% CI: 1.2-10.1). Logistic regression analyses revealed an increase in PTD at <37 weeks for 10 women with late use of ART not containing zidovudine (ZDV; OR = 7.9, 95% CI: 1.4-44.6) and a decrease in adverse pregnancy outcomes as follows: late use of ART containing ZDV was associated with decreased risk for stillbirth and PTD at <37 weeks (OR = 0.06, 95% CI: 0.02-0.18; OR = 0.5, 95% CI: 0.3-0.8, respectively), and ART containing nucleoside reverse transcriptase inhibitors but not ZDV during early and late pregnancy was associated with decreased risk for PTD at <32 weeks (OR = 0.3, 95% CI: 0.2-0.7). Benefits of ART continue to outweigh observed risks.

Addenbrooke's reunion.

It will be ten years this year since the September 1975 set qualified at Addenbrooke,s Hospital, Cambridge.

Zidovudine resistance phenotype and risk of perinatal HIV-1 transmission in zidovudine monotherapy-treated mothers with moderately advanced disease.

The association of phenotypic zidovudine resistance with perinatal transmission was evaluated in 74 zidovudine-treated mothers enrolled in the Women and Infants Transmission Study through September 1994. Women in the sample had moderately advanced disease, with a median CD4+ cell count of 271/microL and a median plasma HIV-1 RNA level of 39,811 copies/mL. Factors independently associated with zidovudine resistance at delivery (50% inhibitory concentration [IC50], >/=0.1 microM) in multiple logistic regression included prepregnancy zidovudine use, high log plasma HIV-1 RNA level, and low CD4+ cell count. Of 74 mothers, 16 (22%) transmitted HIV-1 to their infants. After adjustment for duration of membrane rupture and CD8+ cell count, zidovudine resistance (IC50 range, 0.01-2.2 microM) was associated with an increased odds of transmission (ORadj, 1.25 per 0.1 microM; 95% confidence interval, 1.01-1.54), suggesting a decreased effect of prenatal zidovudine on preventing transmission in mothers infected with zidovudine-resistant virus. However, when the analysis was limited only to those mothers infected with virus containing zidovudine resistance mutations, no association between phenotypic resistance and transmission remained, indicating that phenotype may not provide significant additional information in predicting transmission where resistance genotype is known.

Association of HIV-1 viral phenotype in the MT-2 assay with perinatal HIV transmission.

A case-control design study was used to investigate the association of maternal HIV-1 phenotype in MT-2 cells at or near the time of delivery with perinatal transmission of HIV-1, controlling for maternal CD4 percentage and duration of rupture of membranes, in 48 transmitting and 96 non-transmitting HIV-1-infected mothers who gave birth between 1990 and 1995. The non-syncytium-inducing (NSI) phenotype was more commonly seen in transmitting mothers compared with non-transmitting mothers (90% vs. 75%, p =.04). In a multivariable logistic regression model, the following maternal characteristics were significantly associated with HIV transmission: NSI phenotype (odds ratio [OR] = 6.08; 95% confidence interval [CI]: 1.73-21.35) and log(10) viral load (OR = 2.11; CI: 1.19-3.74). Finally, the association of NSI phenotype with transmission was stronger in transmitting women who received azidothymidine during pregnancy compared with transmitters who did not.

Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission.

CONTEXT: The Women and Infants Transmission Study is a prospective natural history study that has been enrolling HIV-1-infected pregnant women and their infants since 1989. OBJECTIVE: To evaluate the impact of different antiretroviral regimens on perinatal HIV-1 transmission at the population level. DESIGN: Prospective cohort study. Plasma HIV-1 RNA levels were serially measured in 1542 HIV-1-infected women with singleton live births between January 1990 and June 2000. MAIN OUTCOME MEASURE: HIV-1 status of the infant. RESULTS: HIV-1 transmission was 20.0% (95% confidence interval [CI], 16.1%-23.9%) for 396 women who not receiving prenatal antiretroviral therapy; 10.4% (95% CI, 8.2%-12.6%) for 710 receiving zidovudine monotherapy; 3.8% (95% CI, 1.1%-6.5%) for 186 receiving dual antiretroviral therapy with no or one highly active drug (Multi-ART); and 1.2% (95% CI, 0-2.5%) for 250 receiving highly active antiretroviral therapy (HAART). Transmission also varied by maternal delivery HIV RNA level: 1.0% for <400; 5.3% for 400 to 3499; 9.3% for 3500 to 9999; 14.7% for 10,000 to 29,999; and 23.4% for >30,000 copies/mL (p =.0001 for trend). The odds of transmission increased 2.4-fold (95% CI, 1.7-3.5) for every log10 increase in delivery viral load. In multivariate analyses adjusting for maternal viral load, duration of therapy, and other factors, the odds ratio for transmission for women receiving Multi-ART and HAART compared with those receiving ZDV monotherapy was 0.30 (95% CI, 0.09-1.02) and 0.27 (95% CI, 0.08-0.94), respectively. CONCLUSION: Levels of HIV-1 RNA at delivery and prenatal antiretroviral therapy were independently associated with transmission. The protective effect of therapy increased with the complexity and duration of the regimen. HAART was associated with the lowest rates of transmission.

Immune parameters and morbidity in hard drug and human immunodeficiency virus-exposed but uninfected infants.

OBJECTIVE: To examine the association of maternal hard drug use (injection drugs, cocaine, and opiates) on lymphocyte subsets and clinical morbidity in uninfected infants who are born to human immunodeficiency virus-infected mothers who were enrolled in the Women and Infants Transmission Study (1990-2000). METHODS: Maternal hard drug use was identified by self-report and/or urine toxicology. Infant evaluations occurred at birth and at 1, 2, 4, 6, 9, 12, 18, and 24 months of age. RESULTS: A total of 401 (28%) of the 1436 uninfected infants were born to drug-using mothers. Maternal CD4 lymphocyte percentage and RNA at delivery were not significantly different between drug users and nonusers. Infants who were born to drug-using mothers had lower mean gestational age (37.8 vs 38.5 weeks) and birth weight (2.9 vs 3.1 kg). Infants with intrauterine drug exposure had lower CD4 lymphocyte percentage over the first 4 months of life after adjusting for covariates and higher natural killer lymphocyte percentage. When the analysis was stratified by time period of entry, the incidence of clinical events was not different between infants who were born to drug users versus nonusers. CONCLUSION: Maternal hard drug use is associated with immunologic changes in infants early in life, although these changes did not seem to be associated with increased risk of infections.

Effect of hard-drug use on CD4 cell percentage, HIV RNA level, and progression to AIDS-defining class C events among HIV-infected women.

In vitro and animal studies suggest that cocaine and heroin increase HIV replication and suppress immune function, whereas epidemiologic studies are inconclusive regarding their effect on HIV infection progression. The authors prospectively examined the association between illicit-drug use and 4 outcome measures (CD4 cell percentage, HIV RNA level, survival to class C diagnosis of HIV infection, and death) in a national cohort of HIV-infected women. Women enrolled between 1989 and 1995 were followed for 5 years and repeatedly interviewed about illicit ("hard")--drug use. Up to 3 periodic urine screens validated self-reported use. Outcomes were compared between hard-drug users (women using cocaine, heroin, methadone, or injecting drugs) and nonusers, adjusting for age, antiretroviral therapy, number of pregnancies, smoking, and baseline CD4 cell percentage. Of 1148 women, 40% reported baseline hard-drug use during pregnancy. In multivariate analyses, hard-drug use was not associated with change in CD4 cell percentage (P = 0.84), HIV RNA level (P = 0.48), or all-cause mortality (relative hazard = 1.10; 95% confidence interval, 0.61-1.98). Hard-drug users did, however, exhibit a higher risk of developing class C diagnoses (relative hazard = 1.65; 95% confidence interval, 1.00-2.72), especially herpes, pulmonary tuberculosis, and recurrent pneumonia. Hard-drug-using women may have a higher risk for nonfatal opportunistic infections.

Evaluation of coxsackievirus infection in children with human immunodeficiency virus type 1-associated cardiomyopathy.

In a matched case-control study of the association between coxsackieviruses and cardiac impairment, 24 human immunodeficiency virus (HIV) type 1-infected children with cardiac impairment were compared with 24 HIV-1-infected control subjects. Serologic evidence of coxsackievirus infection was present in all children, with no significant difference in geometric mean antibody titers between case patients and control subjects. Conditional logistic regression to test for an association between coxsackievirus antibody titer and the presence or absence of cardiac impairment, by any indicator, showed an odds ratio of 1.11 (95% confidence interval, 0.58-2.10; P=.75), indicating no association between coxsackievirus infection and cardiac impairment. Coxsackievirus antibody titers correlated positively with total IgG levels in nonrapid progressors but not in rapid progressors. Paired serum samples taken before and after diagnosis of cardiac impairment in 5 patients showed no evidence of intervening coxsackievirus infection. These results do not identify a causal role for coxsackieviruses for cardiomyopathy in HIV-1-infected children.

Pharmacokinetics of saquinavir plus low-dose ritonavir in human immunodeficiency virus-infected pregnant women.

The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng. h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC(12)s) during gestation (29,373 +/- 17,524 ng. h/ml [mean +/- standard deviation]), during labor and delivery (26,189 +/- 22,138 ng. h/ml), and during the postpartum period (35,376 +/- 26,379 ng. h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC(12), 7,811 and 13,127 ng. h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P

Multicenter evaluation of use of dried blood and plasma spot specimens in quantitative assays for human immunodeficiency virus RNA: measurement, precision, and RNA stability.

Eleven laboratories evaluated the use of dried blood and plasma spots for quantitation of human immunodeficiency virus (HIV) RNA by two commercially available RNA assays, the Roche Amplicor HIV-1 Monitor and the bioMerieux NucliSens HIV-1 QT assays. The recovery of HIV RNA was linear over a dynamic range extending from 4,000 to 500,000 HIV type 1 RNA copies/ml. The Monitor assay appeared to have a broader dynamic range and seemed more sensitive at lower concentrations. However, the NucliSens assay gave more consistent results and could be performed without modification of the kit. HIV RNA was stable in dried whole blood or plasma stored at room temperature or at -70 degrees C for up to 1 year. Dried blood and dried plasma spots can be used as an easy and inexpensive means for the collection and storage of specimens under field conditions for the diagnosis of HIV infection and the monitoring of antiretroviral therapy.

The relationship of pregnancy to human immunodeficiency virus disease progression.

OBJECTIVE: This study was undertaken to determine the effect of pregnancy on progression of human immunodeficiency virus (HIV) disease. STUDY DESIGN: We compared the immunologic, clinical, and virologic courses of 953 women who had no additional pregnancy after their index pregnancy, with the courses of 329 women who had a second pregnancy subsequent to their index pregnancy. Baseline variables included use of antiretroviral therapy, and CD4 and HIV RNA values. A linear spline growth curve model was used to describe trajectories of variables. The Cox proportional hazards model was used to assess selected covariates on the time to development of clinical class C events or death. RESULTS: Women with repeat pregnancies were less likely to be on antiretroviral therapy at baseline and had a higher CD4% count immediately after their first delivery. The average trajectory of CD4 values in the one-pregnancy group was almost identical to the average trajectory in the repeat pregnancy group. RNA levels in the single-pregnancy group started higher but ended lower than in the second-pregnancy group, although slope differences were modest. There were no significant differences in time to class C events, although women in the repeat-pregnancy group tended to survive longer. CONCLUSION: Repeat pregnancies do not have significant effects on the course of HIV disease.

Mother-to-child transmission of HIV-1: strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms.

The transmission of HIV-1 from mother to child during pregnancy is unlike other types of HIV-1 transmission because the child shares major histocompatibility complex (MHC) genes with the mother during a time while the mother is induced to tolerate the paternally derived fetal MHC molecules, in part through natural killer (NK) recognition of MHC polymorphisms. The relevance of these immune mechanisms to HIV-1 transmission was assessed by determining the HLA-B alleles of mother and infant. Almost half (48%) of mothers who transmitted with low viral loads had HLA-B*1302, B*3501, B*3503, B*4402, or B*5001 alleles, compared with 8% of nontransmitting mothers (P=0.001). Conversely, 25% of mothers who did not transmit despite high viral loads had B*4901 and B*5301, vs. 5% of transmitting mothers (P=0.003), a pattern of allelic involvement distinct from that influencing HIV-1 infection outcome. The infant's HLA-B alleles did not appear associated with transmission risk. The HLA-B*4901 and B*5301 alleles that were protective in the mother both differed respectively from the otherwise identical susceptibility alleles, B*5001 and B*3501, by 5 amino acids encoding the ligand for the KIR3DL1 NK receptor. These results suggest that the probable molecular basis of the observed association involves definition of the maternal NK recognition repertoire by engagement of NK receptors with polymorphic ligands encoded by maternal HLA-B alleles, and that the placenta is the likely site of the effect that appears to protect against transmission of maternal HIV-1 through interrelating adaptive and innate immune recognition.