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PubMed2006

Peptide-loaded dendritic-cell vaccination followed by treatment interruption for chronic HIV-1 infection: a phase 1 trial.

Immune response enhanced by therapeutic HIV-1 vaccine may control viral proliferation after discontinuation of highly active antiretroviral therapy (HAART). Although which strategies for therapeutic vaccination are feasible remains controversial, application of dendritic cells (DCs) as a vaccine adjuvant represents a promising approach to improving deteriorated immune function in HIV-1-infected individuals. The safety and efficacy of DC-based vaccine loaded with HIV-1-derived cytotoxic T lymphocytes (CTL) peptides were thus investigated in this study. Autologous DCs loaded with seven CTL peptides with HLA-A*2402 restriction were immunized to four HIV-1-infected individuals under HAART. In terms of safety, peptide-loaded DCs were well tolerated, and only mild local and general symptoms were observed during vaccine administration. ELISPOT assays to detect IFN-gamma production in CD8(+) lymphocytes revealed a limited breadth of responses to immunized peptides in two of four participants, but no response in the remaining two participants. Differences in immunological response might be attributable to the fact that responders displayed higher nadir CD4 counts before starting HAART and were immunized with a larger number of DCs per reactive peptide than non-responders. Discontinuation of HAART after vaccination failed to lower viral set points compared to those before starting HAART. This early outcome warrants further exploration to elucidate the therapeutic value of vaccination with DCs in HIV-1 infection.

Adult↗

PubMed2004

Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients.

Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Abeta species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Abeta species detected in rapidly autopsied brains (<3 h) with sporadic AD were Abeta(1-x) and Abeta(1-42), as well as Abeta(x-42). To establish a linkage between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Abeta(1-x) and Abeta(1-42) production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Abeta loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Abeta production and enhanced deposition of amyloid plaques in sporadic AD patients.

Alzheimer Disease↗

PubMed1990

cis-acting determinants of c-myc mRNA stability.

Rapid turnover of the c-myc message mediates both the low basal level of mRNA and the rapid response to changes in transcription. The primary RNA instability determinant (RID sequence) resides in the 3' untranslated region (UTR), within an 80 base region that is rich in A and U residues. In contrast to granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA in which the RID sequence has been mapped to a repeating AUUUA sequence, mutation of the only copy of this sequence in the c-myc 3' UTR has no effect on RNA turnover. Thus the c-myc RID sequence appears to be quite different from that of GM-CSF, which may account for the differential regulation of half-life exhibited by these mRNAs. c-myc mRNA turnover is also tightly coupled to translation since translational inhibitors stabilize this mRNA. Mutation of the initiating AUG to a termination codon stabilizes c-myc RNA, arguing that loading with polysomes (perhaps accompanied by localization on the cytoskeleton) is also required for proper message turnover.

Animals↗

PubMedDate not supplied

Effective interferon therapy for chronic hepatitis C patients with low viral loads.

BACKGROUND/AIMS: Possible short-term interferon therapy was investigated in chronic hepatitis C patients with genotype 2a or 2b and low viral-loads. Furthermore, initial changes of hepatic C virus RNA levels in early phase interferon therapy, and the number of pretreatment mutated clones at hypervariable region-1 were determined in order to upgrade interferon therapy efficacy prediction rates. METHODOLOGY: Study subjects were 31 patients with histologically proven chronic hepatitis C, having less than 1 Meq/mL of hepatic C virus RNA levels. Daily dose was defined as 9 MU of interferon; patients with genotype lb were treated for 26 weeks, while those with genotype 2a or 2b were treated for 16 weeks. RESULTS: Sustained response rates showed no difference in efficacy between the 2 groups (66.7% vs. 62.5%). Response rates based on the number of hypervariable region-1 clones indicated that the fewer the number of mutated clones, more significant was the increase in efficacy. Efficacy as hepatic C virus RNA in early phase treatment showed no difference in response rates between negative and positive groups at any time point from day 1. CONCLUSIONS: In a low viral-load group, the number of hypervariable region-1 clones was a critical factor influencing interferon therapy efficacy. Thus, 16-week interferon therapy was effective and economical.

Adult↗

PubMed2004

Retrospective analysis of antiretroviral HIV treatment success based on medical history or guided by the reverse hybridisation LiPA HIV genotyping system.

The changes in viral load and CD4(+) count at 3 and 6 months in a group of 166 HIV-infected patients was evaluated. The new therapy was chosen based on the medical history procedures for 70 patients, and in 96 patients it was guided by the partial or complete result of the line probe assay (LiPA) HIV RT and Protease resistance tests. The absolute difference from the baseline of the log viral load at 3 and 6 months was significantly different between the two groups when adjusted for baseline viral load (P < 0.0001) and stayed significant when intention-to-treat analysis was carried out (P < 0.001). The absolute difference of the CD4(+) count was not significantly different when adjusted for baseline CD4(+) (P = 0.854, 3 months; P = 0.06, 6 months). The proportion of patients with a viral load </=200 cp/ml in the medical history group (14.5%, 3 months; 15.2%, 6 months) was significantly different from the proportion of responders in the LiPA group (28.7%, 3 months, P = 0.03; 34.7%, 6 months, P = 0.008). In the intention-to-treat population, the difference between the two groups remained significant (P = 0.01). There was no statistical difference between the two groups in terms of adherence (P = 0.88), number of drug failures (P = 0.12) and for the time since starting treatment (in years) (P = 0.48), but there was a significant difference for the number of new drugs in the new regimen (P < 0.0001) and for the pill burden of the treatment (P = 0.0006). A higher antiretroviral HIV treatment success guided by the LiPA HIV genotyping system than that based on the medical history only is reported. Of note, this study reached the same conclusions as previous studies, which all used sequencing.

Adult↗

PubMed2006

Efficacy and potential for resistance selection of antipseudomonal treatments in a mouse model of lung infection by hypermutable Pseudomonas aeruginosa.

Hypermutable Pseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivative PAOdeltamutS are investigated. Groups of 30 mice were treated for 3 days with humanized regimens of ciprofloxacin (CIP), tobramycin (TOB), CIP plus TOB, or placebo, and mortality, total lung bacterial load, and 4x- and 16x-MIC mutants were recorded. The rates of mutation and the initial in vivo frequencies of mutants (at the onset of treatment) were also estimated and the in vitro- and in vivo-selected mutants characterized. Since both strains had identical MICs, the same pharmacokinetic/pharmacodynamic (PK/PD) parameters were obtained: area under the 24-h concentration-time curve (fAUC)/MIC = 385 for CIP and maximum concentration of drug in serum (fC(max))/MIC = 19 for TOB. Despite adequate PK/PD parameters, persistence of high bacterial numbers and amplification (50,000-fold) of resistant mutants (MexCD-OprJ hyperexpression) were documented with CIP treatment for PAOdeltamutS, in contrast to complete resistance suppression for PAO1 (P < 0.01), showing that conventional PK/PD parameters may not be applicable to infections by hypermutable strains. On the other hand, the efficacy of TOB monotherapy in terms of mortality reduction and bacterial load was very low regardless of the strain but not due to resistance development, since mutants were not selected for PAO1 and were only modestly amplified for PAOdeltamutS. Finally, the CIP-plus-TOB combination was synergistic, further reducing mortality and bacterial load and completely preventing resistance even for PAOdeltamutS (P < 0.01 compared to monotherapy), showing that it is possible to suppress resistance selection in infections by hypermutable P. aeruginosa using appropriate combined regimens.

Animals↗

PubMed2007

Hepatitis B virus genotypes and lamivudine resistance mutations in HIV/hepatitis B virus-coinfected patients.

BACKGROUND: Differences in subtypes, hepatitis B early antigen (HBeAg)-negative variants, and drug resistance mutations all seem to influence the clinical and therapeutic outcome in patients with chronic hepatitis B virus (HBV) infection. Information available on the prevalence and distribution of distinct HBV variants in HIV-positive patients is scarce. METHODS: All HIV-infected patients with persistent serum hepatitis B surface antigen and detectable HBV viremia were identified in a reference HIV clinic located in Madrid, Spain. HBV load, subtypes, precore (PC) and basal core promoter (BCP) variants, and lamivudine (LAM) resistance mutations were analyzed. RESULTS: A total of 81 HBV/HIV-coinfected patients (4.1%) were identified in a population of 1968 HIV-positive patients. Plasma specimens with detectable HBV viremia could be obtained from 62 subjects, and this was the study population that underwent further virologic characterization. HBV genotype distribution was as follows: A (n = 27), D (n = 27), E (n = 1), F (n = 2), and G (n = 3). Two patients had mixed HBV genotypes (A/E and A/F). HBV subtype A was predominant (74%) among patients infected through sexual contact, whereas HBV-D was most frequent (74%) among intravenous drug users (P < 0.001). PC/BCP mutants were more frequent in patients with HBV-D than in those with HBV-A (63% vs. 18%; P < 0.01). Median time on LAM was 40 months; patients with HBV-A tended to show LAM resistance mutations more often (53% vs. 44%) and to develop them earlier (35 vs. 45 months) than patients with HBV-D. The dual L180M + M204V/I mutant was the predominant resistance pattern, although a triple rt173V + 180M + 204V, which acts as a vaccine escape mutant, was found in 1 individual. In the multivariate analysis, patients with LAM resistance mutations were significantly more frequently HBeAg-positive and older than individuals with wild-type HBV. Hepatitis-delta was recognized in 13 (21%) of these 62 HBV viremic patients, with no association with specific HBV variants. CONCLUSION: Risk transmission group, age, and positive serum HBeAg are the main determinants of distinct HBV virologic variants, including HBV genotypes and LAM-resistant mutants, in HBV/HIV-coinfected patients.

Adult↗

PubMed2005

Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021).

Tonus was a pilot study in which previously untreated human immunodeficiency virus type 1 (HIV-1)-infected patients received the combination of abacavir, lamivudine, and tenofovir once a day. There was a high rate of early virological failure, and the M184V and K65R mutations were frequently detected at week 12 (W12). The objective of this study was to examine the selection dynamics of the K65R and M184V/I mutations. Bulk sequencing of the reverse transcriptase (RT) gene was performed on plasma HIV-1 RNA at baseline, W4, and W12 for 21 patients with detectable viral loads. The RT genes from baseline, W4, and W12 plasma samples from five patients who developed both M184V and K65R but with different mutational patterns were also cloned and screened for the K65R mutation by selective real-time PCR. At baseline, bulk sequencing and clonal analysis showed only wild-type RT sequences. At W4, M184V/I was detected in 12/19 patients and K65K/R in 2 patients by bulk sequencing. At W12, M184V/I was found in 18/20 patient, together with the K65R in 13 patients. At W4, clonal analysis revealed the K65R mutation in 0.6 to 48% of clones in the five patients studied. At W12, the K65R mutation was found in 30 to 100% of clones. K65R and M184V/I seemed to arise in separate clones, followed by an enrichment of viruses containing both mutations. The clinical relevance of this independent evolution is unclear. M184V/I was selected more frequently than K65R at W4. However, K65R was also detected early using a clone-sensitive genotyping method. All three nucleoside analogs are known to select the K65R and/or M184V/I mutation. This convergent genetic pathway to resistance, associated with lower antiretroviral potency, may explain the high selection rate of these mutations in this trial.

Adenine↗

PubMed1999

A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a mutation in the bilirubin UDP-glucuronosyltransferase gene.

UNLABELLED: Gilbert syndrome was diagnosed in a girl with anorexia nervosa and unconjugated hyperbilirubinaemia. Since the patient was starved and hyperbilirubinaemic, the loading test was not used for the diagnosis but analysis of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) instead. The patient was homozygous for a missense mutation that replaced guanine with adenine at nucleotide number 211 (211G-->A: G71R). The unconjugated hyperbilirubinaemia was apparently induced by the fasting state. Homozygous missense mutations of the gene have been generally recognized as responsible for Crigler-Najjar syndrome type II; the results obtained here, however, confirm that Gilbert syndrome may also be caused by a homozygous missense mutation of UGT1A1. CONCLUSION: Since anorexia nervosa patients are in a fasting state, they may show moderate unconjugated hyperbilirubinaemia if they have Gilbert syndrome. Gene analysis of such cases will rule out hepatic damage. Homozygous missense mutations of the bilirubin-UDP-glucuronosyltransferase gene cause not only Crigler-Najjar syndrome type II but also Gilbert syndrome.

Anorexia Nervosa↗

PubMed2001

Nanoparticulate systems for the delivery of antisense oligonucleotides.

Antisense oligonucleotides are molecules that are able to inhibit gene expression being therefore potentially active for the treatment of viral infections or cancer. However, because of their poor stability in biological medium and their weak intracellular penetration, colloidal drugs carriers such as nanoparticles were developed for the delivery of oligonucleotides (ODN). ODN associated to nanoparticles were shown to be protected against degradation and to penetrate more easily into different types of cells. As a consequence, nanoparticles were shown to improve the efficiency of ODNs for the inhibition of the proliferation of cells expressing the point mutated Ha-ras gene. In vivo, polyalkylcyanoacrylate (PACA) nanoparticles were able to efficiently distribute the ODNs to the liver whereas the alginate nanosponges could concentrate the ODNs in the lungs. Finally, ODN loaded to PACA nanoparticles were able to improve in mice, the treatment of RAS cells expressing the point mutated Ha-ras gene.

Animals↗

PubMed2004

Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children.

OBJECTIVE: To study the control of viral replication in human immunodeficiency virus (HIV)-infected children on different salvage therapies. DESIGN AND SETTING: A retrospective observational study in 120 HIV-infected children was conducted. The children were divided into 3 groups according to their salvage therapies: (1) children receiving first line highly active antiretroviral therapy (HAART); (2) protease inhibitor-experienced children receiving second line HAART; (3) protease inhibitor-experienced children receiving HAART including lopinavir-ritonavir (LPV/r). The outcome variables examined were time to achieve viral load (VL) < or =400 copies/mL, success in achieving VL < or =400 copies/mL and time to virologic failure (VL >400 copies/mL). METHODS: VL (HIV-RNA copies/mL) was quantified with reverse transcription-polymerase chain reaction molecular assay. For each protocol, survival analyses were conducted to determine the probability of achieving VL < or =400 copies/mL and rebound of VL. RESULTS: VL < or =400 copies/mL was achieved by 52.4% of children receiving first line HAART, 48.3% receiving second line HAART and 71.5% receiving HAART including LPV/r. Children receiving HAART including LPV/r reached VL < or =400 copies/mL in a shorter time than children receiving second line HAART (P = 0.017), but quite similar to children receiving first line HAART. In terms of adjusted relative risk, children receiving HAART including LPV/r were 3.36 [95% confidence interval (95% CI), 1.59, 7.07] more likely to achieve VL < or =400 copies/mL than children receiving a different second line HAART. VL rebound occurred in 68.2% children receiving first line HAART, 73.4% receiving second line HAART and 32.4% receiving HAART including LPV/r. Children receiving HAART that includes LPV/r has less incidence of VL rebound (P=0.013) and 3.29 (95% CI 1.04, 10.3) times less risk to achieve a VL rebound than children receiving a different second line HAART. CONCLUSIONS: HAART that includes LPV/r is able to control HIV replication more efficiently than other classic salvage antiretroviral therapies.

Amino Acid Sequence↗

PubMed1993

A mutation (Trp1193-->Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance.

We evaluated a 35-year-old diabetic male patient with type A insulin resistance, showing acanthosis nigricans. Insulin binding to the patient's Epstein-Barr-virus transformed lymphocytes was mildly reduced. The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. The sequence analysis of amplified genomic DNA revealed that the patient was heterozygous for a mutation substituting Leu for Trp at codon 1193 in exon 20 of the insulin receptor gene. The patient's mother and sister were also heterozygous for a mutation in the insulin receptor gene that substituted Leu for Trp1193 in the beta subunit of the receptor. Therefore, the mutation causes insulin resistance in a dominant fashion. They were less hyperglycaemic and more hyperinsulinaemic than the proband after glucose loading. The mother had diabetes mellitus but did not show acanthosis nigricans, while the sister did not have diabetes and showed acanthosis nigricans. These results suggest that this mutation causes defective tyrosine kinase activity of the insulin receptor, which results in insulin resistance. Insulin action and phenotypic appearance may be mediated by different factors.

Adult↗

PubMed2001

Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas.

The reported frequencies of Gs alpha mutations (gsp mutations) in growth hormone (GH)-secreting pituitary adenomas are variable (ranging from 4.4 to 43%), and the presence of these mutations in the other pituitary adenomas is still a matter of controversy. Previous clinical and biochemical analyses of patients with GH-secreting pituitary adenomas and gsp mutations produced conflicting results and did not demonstrate obvious characteristics. Therefore, we investigated the prevalence of gsp mutations in Korean patients with pituitary adenomas and elucidated the characteristics of these patients. Forty-four GH-secreting adenomas, 7 prolactin (PRL)-secreting adenomas and 32 clinically non-functioning adenomas were examined for the presence of point mutations in codon 201 and 227 of the Gs alpha gene using a nested PCR and direct sequencing of DNA extracted from fresh tissue or paraffin-embedded pituitary adenoma samples. Seven of the 44 GH-secreting pituitary adenomas had point mutations at codon 201 or 227; of these, five mutations were in codon 201 and two were in codon 227. In patients with gsp mutations, mean tumor size was significantly smaller than in patients without gsp mutations (15.9+/-8.7 mm vs. 24.9+/-14.9 mm, P<0.05). Age, sex, basal GH levels, GH response to oral glucose loading, GH response to octreotide and surgical outcome were not different in the two groups. One of the 32 clinically non-functioning pituitary adenomas had a point mutation at codon 201; none of the seven prolactinomas had these mutations. These results show that gsp mutations are not rare in Korean acromegalic patients and mean tumor size is significantly smaller in acromegalic patients with gsp mutations. Our results also confirm the low frequency of gsp mutations in clinically non-functioning pituitary adenomas and the absence of gsp mutations in prolactinoma.

Acromegaly↗

PubMed1996

Mutagenic nitroarenes, diesel emissions, particulate-induced mutations and cancer: an essay on cancer-causation by a moving target.

Initial analyses of the lung tumors seen in rats exposed for their lifetime to elevated levels of the emissions of diesel engines suggested that they were due to powerful mutagens and carcinogens (PAHs, nitro PAHS) absorbed onto the diesel particles. However, further studies showed that carcinogenicity occurred only under conditions that resulted in impaired lung clearance ('overloading') leading to inflammatory reactions and other pathologic sequelae. These observations together with the findings that carbon black, a model for diesel particles devoid of organic mutagens and carcinogens, also induced lung cancers under conditions of overloading led to the suggestion that the cancers resulted from a non-genotoxic mechanism. However, the further finding that inert particulate carcinogens devoid of organics, induce mutations has led to a re-evaluation of the role of mutations in lung carcinogenesis caused by particles and the relevance of the rat model to humans. This is especially timely as epidemiological studies suggest that humans may develop lung cancers following occupational exposure to diesel emission by a mechanism unlikely to involve lung overloading. Finally, the recent recognition that environmental PM-10 (respiratory size particles) may be responsible for a significant portion of human morbidity and mortality, ensures that the health effect of diesel emissions will continue to receive scrutiny as they contribute to the PM-10 load.

Animals↗

PubMed2004

Essential benefits of nucleoside analogue regimens in failing therapy.

Since the introduction of highly active antiretroviral therapy, nucleoside and more recently nucleotide reverse transcriptase inhibitors (NRTIs) have provided a highly effective backbone to antiretroviral regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Nonetheless, treatment failure can result from poor adherence, unfavourable pharmacokinetics, advanced disease or infection with a drug-resistant virus. Recent data have also indicated a high risk of virological failure with triple NRTI regimens, reflecting overall lower potency compared to combinations of NRTIs with either NNRTIs or PIs. Resistance mutations emerging upon failure can cause extensive cross-resistance among available NRTIs, and potentially affect susceptibility to newly developed antiretroviral drugs. However, despite the emergence of resistance, NRTIs can retain significant antiviral activity in treatment-experienced patients. This may reflect residual direct viral load suppression, as well as indirect effects related to impaired viral fitness of NRTI-resistant mutants and antagonist interactions between resistance mutations.

Antiretroviral Therapy, Highly Active↗

PubMed1996

p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users.

Toombak is a type of snuff used extensively in the Northern Sudan by a virtually non-smoking/nondrinking population. This Sudanese snuff contains inordinately high levels of the tobacco-specific nitrosamines (TSNAs) Nl-nitrosonornicotine (NNN) and (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are considered to be major contributors to the induction of cancers of the aerodigestive tract in tobacco chewers, snuff dippers, and smokers. To determine if toombak use may be associated with the induction of mutations in the p53 tumor suppressor gene, we screened four head and neck squamous cell carcinomas (SCCs) obtained from three toombak-using patients and one non-toombak-using patient using polymerase chain reaction/single-stranded conformational polymorphism analysis and DNA sequencing. p53 mutations were found in tumors resected from two of three toombak-using patients, one at codon 282 (CGGarg-->TGGtrp) and the other in intron 6 (AT-->GC). No p53 mutations were observed in the tumor from the non-toombak-using patient. The observed mutations were similar in spectrum to those induced by nitrosamines in mouse lung tumors. No K-ras (codons 12 and 13) or H-ras (codon 12) mutations were found in any of the tumors. These results suggest that toombak components such as TSNAs may induce p53 mutations in head and neck SCCs and are likely contributors to the tobacco-induced carcinogenic load in humans.

Animals↗

PubMed2006

[New virologic tests and their application in management of chronic hepatitis B].

Virologic testing and clinical management of patients with chronic hepatitis B must take into account the particular characteristics of this virus. These tests rely on the detection of different viral genotypes and mutations that may cause viral escape to either the host immune response or the antiviral treatment. Tests to quantify viral load are important for studying the efficacy of antiviral treatments and especially because the pathogenesis of hepatic lesions requires viral replication. Appropriate management of chronic hepatitis B must rely not only on the standard serologic markers but also on tests that quantify viral load and on the study of viral genome variability according to clinical situation.

Adenine↗

PubMed2004

Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort.

BACKGROUND: Hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was described in association with reverse-transcriptase (RT) mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs). We evaluated the effect of RT mutations associated with hypersusceptibility to NNRTIs on the response to efavirenz-based therapy. METHODS: We analyzed an observational database of patients for whom highly active antiretroviral therapy failed and who received genotypic resistance testing-guided therapy, either efavirenz or protease inhibitor (PI) based. Study end points were achievement of virus load <80 copies/mL, achievement of virus load <80 copies/mL without rebound to >500 copies/mL, and changes in CD4 cell counts. RESULTS: The baseline RT mutations M41L, M184V, L210W, and T215Y and the M41L/T215Y and M41L/T215Y/M184V combinations were associated with virological suppression for efavirenz-treated patients, whereas, for PI-treated patients, only the M184V mutation was associated with virological suppression, and the L210W mutation showed a negative correlation; no correlation was found between any mutation and virological response without rebound. CONCLUSIONS: The M41L, M184V, L210W, and T215Y mutations were associated with a better, although transient, virological outcome in patients treated with efavirenz-based regimens.

Adult↗