Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase.
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Adenine↗
Biomedical subjects
Deenan Pillay
Publications and source records attributed to Deenan Pillay.
HIV-1 pol gene variation is sufficient for reconstruction of transmissions in the era of antiretroviral therapy.
OBJECTIVES: We wished to assess the potential of using HIV-1 pol gene for the identification of transmissions events by phylogenetic means in the era of antiretroviral drug selective pressure. DESIGN: The relatedness of the viruses within a large database of pol sequences generated from HIV-1 infected individuals from the UK was reconstructed by phylogenetic analyses. METHODS: A total of 140 pol sequences were selected out of the 2500 database entries, on the basis of a pairwise genetic distance higher than 95%. Neighbour Joining and Maximum Likelihood trees were implemented. Trees were reconstructed after exclusion of codon positions associated with drug resistance from the original pol alignment. Trees based on the corresponding env and gag genes were implemented to confirm the linkages. RESULTS: Up to 23 transmission clusters were identified, supported by high bootstrap values (> 99), congruent epidemiological data and/or similar drug resistance motifs. The topology of the tree was consistent after exclusion of the drug resistance associated codons. Identical topologies were obtained in trees implemented from gag and env genes alignments. CONCLUSIONS: Despite its genetic conservation, the HIV-1 pol gene holds sufficient variability to permit the phylogenetic reconstruction of transmissions. Identical clusters were obtained whichever of the three principal genes is considered and no bias was induced by the presence of drug resistance mutations. These findings demonstrate the important epidemiological information inherent within routinely collected laboratory data, which can assist in estimating rates of recent HIV-1 transmission within a population.
Anti-HIV Agents↗
Synonymous genetic polymorphisms within Brazilian human immunodeficiency virus Type 1 subtypes may influence mutational routes to drug resistance.
BACKGROUND: Most published data on antiretroviral-drug resistance is generated from in vitro or in vivo studies of subtype B virus. However, this subtype is associated with <10% of HIV infections worldwide, and it is essential to explore subtype-specific determinants of drug resistance. One potential cause of the differences between subtypes is the synonymous codon usage at key resistance positions. METHODS: We investigated the nucleotide sequences at drug resistance-related sites, for all major Brazilian subtypes (B, C, and F1) of human immunodeficiency virus type 1 (HIV-1) group M. RESULTS: We identified a change at positions 151 and 210 of the reverse-transcriptase region in subtype F1, such that the emergence of these key nucleoside/nucleotide analogue resistance mutations required an extra nucleotide change in subtype F1, compared with subtypes B and C. The clinical significance of position 210 was confirmed within a large Brazilian database, in which we identified a lower prevalence of the L210W mutation in subtype F1 virus, compared with subtype B virus, in patients matched for thymidine-analogue experience. An inverse relationship between the L210W and K70R mutations was also observed. CONCLUSIONS: The findings of the present study illustrate an important mechanism by which a subtype may determine genetic routes to resistance, with implications for treatment strategies for populations infected with HIV-1 subtype F.
Base Sequence↗
Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000.
OBJECTIVES: To establish a surveillance programme for HIV drug resistance within the UK covering the years from 1998 to 2000, following the introduction of triple combination antiretroviral therapy. METHODS: Sentinel sites included large, medium sized and small clinical centres. Data were analysed until December 2000. RESULTS: Of nearly 300 samples tested, results from 91, 92 and 92 patients, respectively in 1998, 1999 and 2000, who were receiving HIV therapy with a viral load >2000 copies/mL, the majority had viruses with some degree of drug resistance. Overall, the presence of any resistance increased between 1998 and 1999, and fell again in 2000 (69% versus 88% versus 55%). However, major differences were observed between drug classes, such that non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) resistance rose dramatically over the period studied. We show that this correlated with increased NNRTI prescribing. Furthermore, an overall increase in prevalence of viruses with resistance to one or more drugs within all three available classes was observed. A higher prevalence of drug resistance was observed in patients from smaller clinical centres. CONCLUSIONS: This is the first such sentinel surveillance dataset from the UK, and is unique in correlating these data with national antiretroviral prescribing patterns. Our findings are relevant to the increased transmission of HIV drug resistance observed over this period.
Anti-HIV Agents↗
The effect of highly active antiretroviral therapy for HIV on the anti-HCV specific humoral immune response.
The effect of highly active antiretroviral therapy (HAART) on HCV replication is controversial, with some studies reporting no effect and others increases, reductions and even clearances of HCV RNA after treatment. In this study, the effect of HAART was investigated on the titre of anti-HCV specific antibodies and on the relationship between these antibodies and HCV RNA level in a cohort of 24 patients with inherited bleeding disorders. A significant inverse correlation between antibodies to both total HCV proteins and HCV RNA (R = -0.42, P = 0.05) and between antibodies to HCV envelope glycoproteins and HCV RNA (R = -0.54, P = 0.01) was observed pre-HAART. The relationship disappeared or was obscured after therapy (R = 0.24, P = 0.30 and R = 0.16, P = 0.50, respectively). Thus, we show that HAART affects the HCV specific humoral immune responses without affecting the HCV RNA level.
Animals↗
Transmission of HIV-1 drug resistance.
BACKGROUND: The use of highly-active anti-retroviral therapy (HAART) for treating HIV infections is increasing. Recent studies have demonstrated that HAART is improving both the length and quality of life in HIV-infected patients. Resistant strains of HIV arise when drug adherence is poor. This can lead to the transmission of drug-resistant strains of HIV to susceptible individuals. This can lead to suboptimal first-line therapy, if the resistance profile of the transmitted virus is unknown. OBJECTIVES: To review the mechanisms of how drug resistance arises; the methods used to characterise drug resistance; the problems arising with compliance leading to the development of drug-resistant HIV strains; the evidence for the incidence, prevalence and trends in the transmission of resistant HIV strains in different risk groups; and the evidence of suboptimal response to first-line therapy where transmission of a resistant HIV strain has occurred. On the basis of this, a case is presented for the routine resistance testing of all newly diagnosed HIV-infected individuals. STUDY DESIGN: Literature review. RESULTS AND CONCLUSIONS: There is evidence, though limited at present, that transmission of drug-resistant HIV strains can lead to suboptimal response to first-line therapy in newly diagnosed HIV-infected individuals. As the use of HAART can only increase in the future, and compliance will always be a problem in such HAART-treated patients, baseline resistance testing should become a routine part of their management.
Drug Resistance, Viral↗
Clinically validated genotype analysis: guiding principles and statistical concerns.
Whereas previously the output of HIV resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virological outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and analytical methodology used to derive it. For genotyping, the most widely used resistance tool in clinical practice, these considerations are further complicated by the range of mutational patterns present in the treated population. There is no definitively superior methodology for generating a genotype-response association for use in interpreting a resistance test, and the various approaches used to date all have their strengths and weaknesses. This review discusses the processes involved in constructing such tools, with particular emphasis on establishing validated mutation score rules, and examines the key issues and confounding factors that influence predictive accuracy outside the originating dataset. Since the size of the sample is a key influence on the statistical power to determine an effect, it is hoped that a greater understanding of the influence of study design and methodology will assist the development of standardized outcome measures and reporting formats that allow data pooling at the international level.
Anti-HIV Agents↗
Current patterns in the epidemiology of primary HIV drug resistance in North America and Europe.
Despite numerous studies in recent years, it is still difficult to draw general conclusions about the extent to which drug-resistant HIV-1 is transmitted. In addition to the highly stratified nature of primary resistance itself, true epidemiological surveillance has been rare and studies to date have suffered from wide variability in their designs, definitions and datasets. In the absence of consensus standards, this has resulted in a large number of isolated 'snapshots' with little scope for data-pooling and comparison. This brief review examines some of the major confounding factors that restrict the utility of individual studies and prevent the combination of studies to increase statistical power. Despite these limitations, data from North America and Europe lead to the tentative conclusion that transmission rates in these areas have generally fallen or remained stable in the past 2-3 years. However, data for the UK seem to indicate an ongoing rise in the transmission of drug resistance mutations, currently present in up to 20% of new infections. Transmission of resistant HIV represents a clinically important phenomenon, although the scale and relevance are being obscured by methodological variations and non-clinical definitions of resistance. Those of us with an interest in the epidemiology of drug resistance, whether in primary transmission or on-treatment, must learn to speak the same language if we are to establish meaningful correlations between survey datasets and the HIV-infected population as a whole.
Anti-HIV Agents↗
Reconstitution of the Epstein-Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation.
The recovery of circulating antigen-specific T-cell immunity to Epstein-Barr virus (EBV) was determined in ELIspot assays following allogeneic myeloablative or nonmyeloablative stem cell transplantation (MST/NST). In 8 of 12 MST patients receiving an alemtuzumab-treated graft, the frequency of the EBV-specific reactivities was similar to or greater than that seen in the healthy controls. A response was detectable in 3 of 6 and 6 of 9 patients by 3 and 6 months, respectively, and in all patients by one year following MST. In contrast, only 1 of 9 (95% confidence interval [CI], 0-2.8) patients made a detectable EBV-specific response by 6 months following NST conditioned with fludarabine, melphalan, and alemtuzumab. Responses were detected in 7 of 10 patients by 1 year after NST. Parallel surveillance demonstrated that other virus infections occurred more frequently and earlier after transplantation in NST patients. The use of alemtuzumab in vivo in the nonmyeloablative conditioning might have resulted in the delay in EBV-specific T-cell recovery and increased virus infections.
Alemtuzumab↗
Identification of a transmission chain of HIV type 1 containing drug resistance-associated mutations.
We have investigated a potential transmission chain of HIV-1 with drug resistance-associated mutations between three individuals over a period of 5 years by use of cloning and sequencing of viral genes, and phenotypic characterization. Viruses containing reverse transcriptase drug resistance-associated mutations were transmitted sequentially between three homosexual men (A, B, and C), and persisted in one individual for at least 4 years, despite intermittent therapy and reduced viral replicative capacity compared with wild-type strains. Clonal analysis of the envelope gene from semen and blood virus showed that the virus transmitted to patient C was more closely related to virus from the semen than the blood of patient B. Our data suggest that HIV variants with drug resistance-associated mutations can persist following primary infection, despite intervening antiretroviral therapy, and subsequently sexually transmitted. We provide "proof of principle" that such mutations can therefore become "fixed" within the circulating virus pool.
Anti-HIV Agents↗
Drug resistance genotypes predict response to amprenavir-containing regimens in highly drug-experienced HIV-1-infected patients.
We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.
Adult↗
Drug-resistant HIV-1 in the semen of men receiving antiretroviral therapy with acute sexually transmitted infections.
Sexually transmitted infections may enhance the sexual transmission of HIV-1. It is possible that loss of virological control in patients with such infections receiving antiretroviral therapy (ART) may even facilitate the transmission of drug-resistant HIV. We have recently demonstrated that in those on maximally suppressive ART this effect is reduced. We have examined the virus obtained from the blood plasma and seminal plasma of six HIV-1-infected men receiving poorly suppressive ART with acute urethritis for the presence of drug resistance-associated mutations. In four men with gonorrhoea the blood and seminal plasma HIV-1 had mutations conferring reduced susceptibility to one or more available drugs. In one of these men the viral load of drug-resistant virus in seminal plasma was 20-fold higher during gonorrhoea than following antibiotic treatment, with no change in blood plasma viral load. We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1.
Acute Disease↗
Issues in diagnostic testing and monitoring in HIV/viral hepatitis co-infection.
Co-infection with HIV and hepatitis B (HBV)/ hepatitis C virus (HCV) occurs commonly due to similar routes of transmission. Both hepatotropic viruses can cause a severe clinical picture in HIV-infected individuals with rapid progression of liver disease, cirrhosis and increased mortality. Fortunately, treatment options of HBV and HCV are becoming well established and may have a clinical impact in slowing disease progression. This, coupled with the fact that highly active antiretroviral therapy (HAART) has increased the life expectancy of HIV-infected patients stresses the importance of management of concurrent illnesses such as HBV and HCV infection, taking into consideration pharmacokinetic interaction with components of HAART regimens.
Antibodies, Viral↗
The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients.
The K65R mutation in HIV-1 reverse transcriptase is associated with reduced susceptibility to abacavir and tenofovir. We established its prevalence within a large clinical database, and investigated correlations with other resistance-associated mutations and antiretroviral history. The presence of K65R is associated with previous abacavir use. Although rare, it is preferentially selected within non-thymidine analogue-containing regimens, compared with concurrent zidovudine or stavudine use, which is associated with thymidine analogue mutations. Both genetic routes may compromise abacavir and tenofovir activity.
Adenine↗
Minimal variation in T-20 binding domain of different HIV-1 subtypes from antiretroviral-naive and -experienced patients.
In-vitro differences in T-20 susceptibility among HIV-1 subtypes have been reported. We therefore studied the T-20 binding domain of a variety of virus subtypes from both antiretroviral-naive and -experienced patients. Minimal variation in the HR-1 region of gp41 was observed, especially within the region responsible for T-20 resistance. Any subtype differences in T-20 susceptibility do not appear to be related to HR-1 genetic variation.
Anti-HIV Agents↗
Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial.
The association between virologic response and human immunodeficiency virus type 1 (HIV-1) subtype was investigated in 113 HIV-1-infected children randomly assigned to receive zidovudine plus lamivudine, zidovudine plus abacavir, or lamivudine plus abacavir in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. Symptomatic children (n=68) also received nelfinavir; asymptomatic children (n=45) were randomly assigned to receive nelfinavir or placebo. HIV-1 subtypes A, B, C, D, F, G, H, A/E, and A/G were found in 15%, 41%, 16%, 9%, 5%, 2%, 1%, 5%, and 7% of the children, respectively. Resistance assay failure rates were higher for non-B subtypes than for B subtypes (genotype, P=.01; phenotype, P=.02). HIV-1 subtype was not associated with virologic response at 24 and 48 weeks after initiation of treatment. No differences were observed in the frequency of development of resistance mutations L90M (P=1.00) and D30N (P=.61) in B and non-B viruses. In conclusion, no evidence that subtype determined virologic response to therapy was found.
Antiviral Agents↗
The effects of antiretroviral therapy on HIV-1 RNA loads in seminal plasma in HIV-positive patients with and without urethritis.
BACKGROUND: High seminal plasma HIV-1 RNA loads (SVL) have been reported during gonococcal, non-gonococcal and chlamydial urethritis in patients not taking antiretroviral therapy. OBJECTIVE: To examine if urethritis leads to increased SVL in HIV-positive patients taking antiretroviral therapy. METHODS: Men who had been taking therapy for at least 3 months were recruited: 24 had urethitis (PWU) and 16 were without urethritis (controls). At three visits, 1 week apart, blood plasma viral load (BVL) and SVL were assayed by quantitative polymerase chain reaction or the NASBA assay. RESULTS: Most subjects had undetectable SVL (18 PWU, 13 controls). Among those with undetectable BVL prior to first study visit, virus was undetectable in semen in 5/5 episodes of chlamydial urethritis, 6/7 episodes of non-gonococcal urethritis and 4/5 cases of gonococcal urethritis. Two PWU with undetectable BVL just prior to the first study visit had low to moderate SVL, which became undetectable by visit 2 following treatment. Of nine subjects with detectable SVL, eight had detectable BVL (3/3 controls and 5/6 PWU). Of these, 1/3 controls and 4/5 PWU (all with gonococcal urethritis) had poorly controlled BVL just prior to the first study visit. These four PWU had high SVL and one had higher levels in semen than in blood. This patient's SVL was reduced more than 20-fold following treatment for gonococcal urethritis. CONCLUSIONS: Effective antiretroviral therapy appeared to limit the effect of urethritis on SVL. When BVL was poorly controlled by antiretroviral therapy, high SVL occurred during gonococcal urethritis, increasing the potential risk of transmitting both wild type and drug resistant strains of HIV-1.
Adult↗
Analysis of HIV-1 variation in blood and semen during treatment and treatment interruption.
The variability of populations of human immunodeficiency virus type 1 (HIV-1) in blood and semen, with respect to envelope and polymerase gene sequences, was examined longitudinally in a patient experiencing treatment failure, interruption of treatment, and successful reintroduction of therapy. During treatment failure, there was little evidence of compartmentalisation between blood and semen, with virus with identical resistance-associated mutations observed in both compartments and lack of clustering with respect to envelope gene sequences. After cessation of treatment, wild-type virus became the predominant population, displaying distinct envelope gene populations, indicating that wild-type virus had overgrown the resistant virus, rather than the resistant virus reverting to wild-type. Once successful therapy had been recommenced, it was possible to distinguish distinct populations of virus in the two compartments. These data support the hypothesis that the male genital tract represents a distinct HIV-1 reservoir.
Adult↗