Reduction in human immunodeficiency virus type 1 mutations associated with drug resistance after initiating new therapeutic regimens in pretreated patients

The objective of this study was to investigate the effect of initiating a salvage-therapy regimen on resistant viruses in heavily treated patients infected with human immunodeficiency virus type 1 (HIV-1). Nineteen patients receiving multiple antiretroviral drugs were tested for HIV-1 mutations associated with drug resistance by using an in-house method at baseline and at weeks 2, 4, and 8 of the salvage-therapy regimen. For the majority of mutations analyzed, the mean number of detectable mutations at baseline was significantly higher than the mean at weeks 2, 4, and 8 of salvage therapy. Introducing new and more potent therapy reduces the number of detectable drug resistance-associated mutations within 8 weeks, and no evidence was found that the new therapy promoted the emergence of novel mutations.     

Human immunodeficiency virus type 1 seroprevalence and antiretroviral drug resistance-associated mutations in miners in Gabon, central Africa

Miners in sub-Saharan African are known to have an extremely high prevalence of HIV-1 infection. We therefore evaluated the prevalence of HIV-1 infection among manganese miners in Gabon, central Africa and examined the diversity of HIV-1 strains by characterizing the polymorphism of the pol gene in order to observe drug resistance-associated mutations. In 857 samples tested, the HIV-1 prevalence was 2.9%. By pol sequence analysis, we showed that all the HIV-1 strains belonged to group M, with a majority of CRF02_AG (57%) followed by subtype A (9%) and CRF01_AE or subtype B (4%). The remaining HIV-1 strains demonstrated discordant genomic results and exhibited a mosaic pol genome (30%). Most of the mutations detected in pol coding regions corresponded to the subtype polymorphism, with no specific antiretroviral drug resistance. To avoid the rapid emergence of resistant viruses in this part of central Africa, continuous surveillance of the circulation of drug-resistant viruses must be maintained to guide treatment strategies.     

Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance

To determine the variability of genotypic human immunodeficiency virus (HIV) type 1 drug-resistance interpretation by available expert systems and its clinical implications, 261 subjects for whom a potent antiretroviral regimen was failing who were starting salvage therapy were evaluated. The association of the genotypic susceptibility score (GSS) of the salvage regimen, according to 11 interpretation systems, with HIV RNA outcomes for 6 months was examined. GSS was highly variable, as determined by the different interpretation systems, and showed independent correlation with changes from baseline HIV RNA levels at 6 months with 5 systems--Stanford hivdb, GuideLines 3.0, Retrogram 1.4, HIVresistanceWeb, and S?o Paulo University. Most GSSs predicted virologic response in regimens containing stavudine, lamivudine, efavirenz, or indinavir. Selected systems predicted response in regimens containing didanosine, abacavir, or nelfinavir, and no system predicted outcome of boosted protease inhibitors. GSSs predicted changes in HIV RNA levels better in adherent patients than in nonadherent individuals. Interpretation may be improved, and knowledge should be used uniformly throughout different expert systems.     

Impact of maternal human immunodeficiency virus infection on pregnancy and birth outcomes in Pune, India

Little is known about birth outcomes for HIV-infected women in India. We examine maternal and neonatal birth outcomes in HIV-infected women within the context of enhanced pre-natal care associated with a randomized clinical trial conducted in Pune, India. Birth outcomes of 212 HIV-infected pregnant women were compared with those of 130 HIV-uninfected pregnant women attending a government tertiary care hospital between 2002 and 2004. These women and children were participating in the Six Week Extended-Dose Nevirapine (SWEN) study. Birth outcomes and maternal morbidity data were collected at delivery. We found no differences between HIV-infected and uninfected pregnant women with respect to the proportion with elevated intrapartum blood pressure, eclampsia, oligohydramnios, intrauterine growth restriction (IUGR), preterm delivery, or caesarean section (p>0.05). HIV-infected women were more likely to have peri-partum fever (3% versus 0%, p=0.04). There were no differences in neonatal parameters such as low birth weight (LBW), infants who were small for gestational age, or those having congenital anomalies (p>0.05). Compared with infants of HIV-infected women enrolled antenatally, infants of HIV-infected women enrolled in the post-partum ward had a higher risk of pre-term delivery (20% versus 8%, p=0.02) and LBW (41% versus 22%, p=0.002). HIV-infected women in this cohort in India were not found to have significant negative birth outcomes. Antenatal care was important as those not having received any antenatal care prior to deliver were at increased risk of having a pre-term delivery or an infant with LBW. Based on these data, regular antenatal care provided to HIV-infected women can reduce risk of adverse birth outcomes for their infants.     

Zidovudine resistance mutations and human immunodeficiency virus type 1 DNA burden: Longitudinal evaluation of six patients under treatment

Summary Zidovudine (ZDV) is by far the most widely used drug to counteract human immunodeficiency virus type 1 (HIV-1) infection, both in monotherapy and in combination therapy regimens. However, the majority of patients under prolonged ZDV therapy have been shown to harbour HIV-1 mutant genomes displaying reduced sensitivity to the drugin vitro. In order to investigate the pathogenic role ofin vitro resistance to ZDV, six HIV-1-infected ZDV-treated subjects were evaluated longitudinally (mean follow-up 28.5 months, range 12–39 months) for HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) and for the presence of HIV-1pol gene mutations responsible for ZDV resistance. Quantitation of HIV-1 DNA was performed by competitive polymerase chain reaction (cPCR) and thepol genotype was determined by direct sequencing of PCR products. All of the six patients developed one or more of the HIV-1pol mutations known to confer resistance to ZDVin vitro (Met41Leu, Asp67Asn, Lys70Arg, Thr215Phe/Tyr, Lys219Gln/Glu). A temporal association was found between HIV-1 DNA burden and the level of ZDV resistance, as predicted on the basis of thepol genotype (genotypic resistance). Both virus load and ZDV resistance were inversely correlated with CD4+ cell counts. These results are compatible with a directin vivo pathogenetic role forpol gene mutations shown to be involved in resistance to ZDVin vitro. Monitoring the degree of genotypic resistance to ZDV and to other antiretroviral drugs should be considered in designing protocols for the management of treated patients.

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Zidovudine Resistenz-Mutationen und HIV-Typ1-DNA-Last; Longitudinale Studie unter der Therapie bei sechs Patienten

Zusammenfassung Zidovudin (ZDV) ist das Medikament, das weitaus am häufigsten in Monotherapie oder Kombinationstherapie zur Behandlung von Infektionen durch HIV-1 eingesetzt wird. Unter Langzeitbehandlung mit ZDV wurden jedoch bei der Mehrzahl der Patienten HIV-1-Mutanten mit reduzierterIn-vitro-Empfindlichkeit gegen das Medikament nachgewiesen. Um die pathogene Bedeutung derIn vitro-Resistenz gegen ZDV zu untersuchen, wurden die HIV-1 DNA-Last in mononukleären Zellen des peripheren Blutes und das Vorliegen von für die ZDV-Resistenz verantwortlichen HIV-1pol-Genmutationen bei sechs HIV-infizierten Patienten unter ZDV-Therapie in einer Längsschnittstudie (mit mittlerer Beobachtungszeit von 28.5 Monaten, Bereich 12–39 Monate) gemessen. Die quantitative Bestimmung der HIV-1 DNA erfolgte durch kompetitive Polymerasekettenreaktion (cPCR). Derpol-Genotyp wurde durch direkte Sequenzierung der PCR-Produkte ermittelt. Alle sechs Patienten entwickelten eine oder mehrere der HIV-1 Mutationen, deren Assoziation mitIn vitro-Resistenz gegen ZDV bekannt ist (Met41Leu, Asp67Asn, Lys70Arg, Thr215Phe/Tyr, Lys219Gln/Glu). Zwischen dem auf der Basis derpol-Genotypen (Genotypresistenz) vorhergesagten Spiegel der ZDV-Resistenz und der HIV-1 DNA-Last fand sich eine zeitliche Assoziation. Sowohl die Viruslast wie auch die ZDV-Resistenz standen in umgekehrter Beziehung zu den CD4+-Zellzahlen. Diese Ergebnisse sind mit direkten pathogenenin vivo-Effekten der für die ZDV-Resistenzin vitro verantwortlichenpol-Genmutationen vereinbar. Das Monitoring des Ausmaßes genotypischer Resistenz gegen ZDV und andere antiretrovirale Substanzen sollte bei der Entwicklung von Behandlungsprotokollen berücksichtigt werden.