Person:

McIntosh, Kenneth

Background: The association between baseline drug resistance mutations and subsequent increase in viral failure has not been established for HIV-infected children. We evaluated drug resistance mutations at 39 codon sites (21 protease inhibitor (PI) resistant codons and 18 nucleoside reverse transcriptase inhibitor (NRTI) resistant codons) for 92 clinically stable NRTI-experienced, PI-naive HIV-infected children 2 to 17 years of age who were initiating new therapy with ritonavir plus zidovudine (ZDV) and lamivudine or plus stavudine. The association between baseline drug resistance mutations and subsequent viral failure after 12 and 24 weeks of highly active antiretroviral therapy (HAART) was studied. Results: There were few primary PI associated mutations in this PI-naïve population, but 84% had NRTI mutations – codons 215 (66%), 41 (42%), 67 (37%), 210 (33%) and 70 (32%). None of the specific baseline drug resistance mutations were associated with a higher rate of virologic failure after 12 or 24 weeks of HAART. Median week 12 viral load decreased as the total number of NRTI mutations at baseline increased (P = 0.006). Specifically, a higher level of baseline ZDV resistance mutation was associated with a decrease in viral failure after 12 weeks on a ZDV-containing HAART regimen (P = 0.017). Conclusion: No increase was seen in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. This paradoxical result may be due to adherence, replicative capacity, or ZDV hypersusceptibility to the new regimen.

Objectives: To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women. Design: Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis. Setting: 27 hospitals in Thailand.Participants: 1,436 HIV-infected pregnant women in PHPT-1.Intervention: Zidovudine prophylaxis initiation at 28 or 35 wk gestation. Outcome measures: Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load. Results: Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts. Conclusion: Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV.

Background: Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia. Methods: We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana. Results: A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure–risk difference, −0.69% (95% confidence interval [CI] −2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI −1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93). Conclusions: Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1–6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants. ClinicalTrials.gov Registration Numbers NCT01086878 (http://clinicaltrials.gov/show/NCT01086878), NCT00197587 (http://clinicaltrials.gov/show/NCT00197587), and NCT00270296 (http://clinicaltrials.gov/show/NCT00270296).

BACKGROUND: The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown. METHODS: We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, > or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine. RESULTS: The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group. CONCLUSIONS: All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%.

Background: Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand. Methods and Findings: The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported. Conclusions: The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings. Trial registration ClinicalTrials.gov NCT00162682 Please see later in the article for the Editors' Summary

Background: Antiretroviral treatments decrease HIV mother-to-child transmission through pre/post exposure prophylaxis and reduction of maternal viral load. We modeled in-utero and intra-partum HIV transmissions to investigate the preventive role of various antiretroviral treatments interventions. Methods: We analysed data from 3,759 women-infant pairs enrolled in 3 randomized clinical trials evaluating (1) zidovudine monotherapy, (2) zidovudine plus perinatal single-dose nevirapine or (3) zidovudine plus lopinavir/ritonavir for the prevention of mother-to-child transmission of HIV in Thailand. All infants were formula-fed. Non-linear mixed effect modeling was used to express the viral load evolution under antiretroviral treatments and the probability of transmission. Results: Median viral load was 4 log10 copies/mL (Interquartile range: 3.36–4.56) before antiretroviral treatments initiation. An Emax model described the viral load time-course during pregnancy. Half of the maximum effect of zidovudine (28% decrease) and lopinavir/ritonavir (72% decrease) were achieved after 98 and 12 days, respectively. Adjusted on viral load at baseline (Odds ratio = 1.50 [95% confidence interval: 1.34, 1.68] per log10 copies/mL increment), antiretroviral treatments duration (OR = 0.80 [0.75, 0.84] per week increment) but not the nature of antiretroviral treatments were associated with in-utero transmission. Adjusted on gestational age at delivery (<37 weeks, OR = 2.37 [1.37, 4.10]), baseline CD4 (Odds ratio = 0.79 [0.72, 0.88] per 100 cells/mm3 increment) and predicted viral load at delivery (OR = 1.47 [1.25, 1.64] per log10 copies/mL increment), single-dose nevirapine considerably reduced intra-partum transmission (OR = 0.32 [0.2, 0.51]). Conclusion: These models determined the respective contributions of various antiretroviral strategies on prevention of mother-to-child transmission. This can help predict the efficacy of new antiretroviral treatments and/or prevention of mother-to-child transmission strategies particularly for women with no or late antenatal care who are at high risk of transmitting HIV to their offspring. Trial Registration This analysis is based on secondary data obtained from three clinical trials. ClinicalTrials.gov. NCT00386230, NCT00398684, NCT00409591.

Abstract Background. We assessed the incidence of tuberculosis, risk factors for tuberculosis, and the contribution of tuberculosis on mortality in a large cohort of human immunodeficiency virus (HIV)-infected children <15 years of age initiating first-line antiretroviral therapy (ART) between 1999 and 2012 in Thailand, one of the 22 high tuberculosis burden countries. Methods. A physician reviewed and classified tuberculosis cases. Incidence was the number of children with incident tuberculosis, defined as a first or recurrent tuberculosis diagnosis >30 days after ART initiation, divided by the total person-years of follow-up (PYFU). Risk factors for incident tuberculosis were identified using Fine and Gray’s competing risks models, with death from other causes treated as a competing event, and risk factors for death were identified using Cox models. Results. At ART initiation, 670 children (55% female) had a median age of 6.4 years (interquartile range, 2.0–9.6), body mass index-for-age z-score −0.8 (−1.9 to 0.0), HIV ribonucleic acid viral load 5.1 log10 copies/mL (4.6–5.6), and CD4 9% (3–17). Median duration of follow-up was 7.7 years. Tuberculosis incidence was 7 per 1000 PYFU (95% confidence interval [CI], 5–11) and decreased with ART duration. Lower age-adjusted hemoglobin, hematocrit, and CD4 at ART initiation were associated with a higher risk of incident tuberculosis. Of the 30 incident tuberculosis cases, 9 died. Diagnosis of incident tuberculosis was associated with mortality (unadjusted hazard ratio = 10.2, 95% CI = 4.8–21.5, P < .001 and adjusted hazard ratio = 5.4, 95% CI = 2.5–11.7, P < .001). Conclusions. Incident tuberculosis was strongly associated with mortality. CD4 counts or hemoglobin or hematocrit levels may prompt clinicians to consider a possible tuberculosis infection.