Safety of 6-week Neonatal Triple-combination Antiretroviral Postexposure Prophylaxis in High-risk HIV-exposed Infants
Suvaporn AnugulruengkittPiyarat SuntarattiwongPradthana OunchanumUssanee SrirompotongWatsamon JantarabenjakulJiratchaya SophonphanSunti PunnahitanonChitsanu PancharoenTim R. CresseyKulkanya ChokephaibulkitThanyawee Puthanakit
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Combination antiretroviral drug regimens are increasingly preferred for neonatal postexposure prophylaxis (PEP) among HIV-exposed infants with high-risk of transmission. We evaluated the adverse events associated with the use of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP) for neonatal PEP during the first 6 weeks of life.A prospective cohort of non-breast-fed HIV-exposed infants was conducted at 5 clinical sites in Thailand. Study population included 100 high-risk HIV-exposed infants (maternal HIV RNA > 50 copies/mL prior to delivery or received antiretroviral therapy less than 12 weeks) and 100 low-risk HIV-exposed neonates. High-risk infants received ZDV/3TC/NVP for 6 weeks whereas low-risk HIV-exposed neonates received a 4-week regimen of ZDV. Complete blood count, aspartate transaminase and alanine transaminase were assessed at birth, 1, 2 and 4 months of life.From October 2015 to November 2017, 200 infants were enrolled, of which 18.5% had low birth weight < 2500 g. The proportion of infants with anemia grade 2 or higher at 1 and 2 months of life between ZDV/3TC/NVP and ZDV prophylaxis was 48.5% vs 32.3% (P=0.02); nevertheless, severe anemia (grade 3) was not significantly different; 9.2% vs 10.2% (P=0.81), respectively. At 1 month old, infants on ZDV/3TC/NVP prophylaxis had significantly higher grade 2 anemia versus infants on ZDV alone (33.0% vs 13.4%; P=0.001); however, no difference was observed at 2 months old. No differences in neutropenia or hepatotoxicity between infant prophylactic regimens were observed.Triple antiretroviral neonatal PEP with ZDV/3TC/NVP for 6 weeks in high-risk HIV-exposed infants did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy prophylaxis.Keywords:
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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To examine the efficacy of the Stavudine, Lamivudine and Nevirapine (SLN) regime in the initial treatment of HIV infection and AIDS in adults.
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The objective of this study was to determine the efficacy and safety of adding zidovudine to continuous treatment with lamivudine in symptomatic human immunodeficiency virus type 1 (HIV-1)-infected patients. Forty patients were monitored throughout lamivudine monotherapy and subsequent combination therapy with lamivudine and zidovudine, which was initiated because of disease progression, declining CD4 cell counts or prolonged use of lamivudine. Eleven of these patients had been treated with zidovudine before the start of the study. The median CD4 cell count at the start of lamivudine monotherapy was 200 x 10(6) cells/l. After a median interval of 69 weeks (range 23-102 weeks), the median CD4 cell count had dropped to 110 x 10(6) cells/l. Initial improvements in all laboratory markers for antiretroviral efficacy were observed after the addition of zidovudine. The median CD4 cell count remained 18% above baseline after 48 weeks of treatment with lamivudine and zidovudine, however plasma HTV-1 RNA load and CD4 cell counts returned towards baseline during prolonged treatment in most patients. The combination was well tolerated, although anaemia was observed in nine patients. Repeated measures analysis of variance suggested a superior effect of lamivudine monotherapy in patients who had previously used zidovudine. In conclusion, zidovudine was found to be effective in patients who have been treated with lamivudine. The study stresses the need to further define the mechanisms underlying this prolonged antiviral effect.
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The efficacy of regimens that include both zidovudine and nevirapine can be explained by the synergistic interactions between these drugs. N348I in HIV-1 reverse transcriptase confers decreased susceptibility to zidovudine and nevirapine. Here, we demonstrate that N348I reverses the synergistic inhibition of HIV-1 by zidovudine and nevirapine. Also, the efficiency of zidovudine-monophosphate excision in the presence of nevirapine is greater for N348I HIV-1 reverse transcriptase compared with the wild-type enzyme. These data help explain the frequent selection of N348I in regimens that contain zidovudine and nevirapine, and suggest that the selection of N348I should be monitored in resource-limited settings where these drugs are routinely used.
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Susceptibility to zidovudine and lamivudine was determined on human immunodeficiency virus type 1 (HIV-1) isolates obtained from patients who added lamivudine after 6 months of treatment with zidovudine. Lamivudine-resistant isolates that were also zidovudine-resistant were recovered from 13/16 (81%) patients after 6 months of dual therapy. In contrast to findings in anti-retroviral therapy-naive patients, these results suggest that dual resistance to zidovudine and lamivudine emerges relatively quickly when lamivudine is added to zidovudine as a single agent in the majority of patients with extensive prior zidovudine treatment.
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Presence of mutations associated with resistance to zidovudine or lamivudine was determined in isolates of HIV-1 obtained after long-term follow-up of 64 infected individuals who received zidovudine, lamivudine, or both drugs as initial antiretroviral therapy. Zidovudine resistance mutations were less frequent in isolates from patients treated with combination lamivudine plus zidovudine compared with zidovudine alone, but these mutations accumulated over time. Phenotypic resistance to both drugs was found in isolates from 3 of 23 patients. In 3 other patients, lamivudine-resistant virus detected at week 12 was replaced by wild-type virus after longer follow-up, which correlated with a return to baseline levels of plasma HIV-1 RNA. These results show that dual resistance to zidovudine and lamivudine develops over time despite the delayed emergence of zidovudine-resistant mutations. These results also suggest a selective advantage in vivo for HIV-1 species that are wild-type at RT codon 184.
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Objective To study zidovudine resensitization and dual resistance to zidovudine/lamivudine in HIV-1 isolates from nucleoside reverse transcriptase (RT) inhibitor-experienced patients during selective pressure exerted by zidovudine/lamivudine combination therapy. Design and methods HIV-1 isolates from 29 patients receiving zidovudine/lamivudine combination therapy in the Delta roll-over study were analysed at entry and during a 1 year follow-up period for phenotypic susceptibility to zidovudine and lamivudine in the ANRS PBMC assay. The RT gene from codon 20 to 230 and at codon 333 was analysed by nucleotide sequencing of the corresponding isolates. Results HIV-1 isolates from 23 of the 29 patients were phenotypically resistant to zidovudine at baseline; 61% of these patients showed significant zidovudine resensitization during follow-up. The zidovudine IC 50 value correlated positively with log 10 plasma HIV-1 RNA ( P=0.02) and negatively with the CD4 cell count ( P=0.004). Zidovudine resensitization (related to acquisition of the M184V mutation) was transient, with evolution towards dual resistance to zidovudine and lamivudine in 20 of the 29 patients. The phenotype of certain dually resistant isolates coincided with the emergence of multiple mutations in the 5’ part of the RT gene. Conclusions M184V-mediated zidovudine resensitization of HIV-1 is transient in most patients who are given zidovudine/lamivudine combination therapy when zidovudine resistance has already emerged. The subsequent evolution towards dual phenotypic resistance to zidovudine/lamivudine corresponds to complex genotypic profiles.
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Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV.We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine-nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine-placebo regimen); and in the last, mothers and infants received placebo (placebo-placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing.Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan-Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine-nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo-placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine-nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine-placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy.A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV.
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To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy.In a randomized, double-blind study, 173 antiretroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) > 400 copies/ml could add other antiretrovirals. From weeks 11 to 48, samples with vRNA > 400 copies/ml were collected for genotyping and phenotyping.At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was > 400 copies/ml in seven of 72 (10% patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n = 3 cases), WT (n = 3) and M184V plus thymidine analogue mutations (TAMs) (n = 1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n = 37), WT ( n= 1) and M184V plus TAMs (n = 3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA < 400 copies/ml (intent-to-treat with missing = failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1-2 log,10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively.Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.
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(1) Combivir is a fixed-dose combination of two HIV reverse transcriptase inhibitors: zidovudine (300 mg) + lamivudine (150 mg). (2) A meta-analysis of four trials shows that this combination is more effective clinically than zidovudine monotherapy. One trial also shows that clinical efficacy is even better with the triple combination of the protease inhibitor indinavir with zidovudine + lamivudine. (3) The risk of anaemia and neutropaenia necessitates blood cell monitoring during treatment. (4) Compared with lamivudine and zidovudine taken separately, Combivir does not reduce the frequency of doses (two a day), but the daily number of tablets falls from four to two, provided that the patient does not require dose adjustment.
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