Daily news feed on HIV drug resistance-related topics
Past 2003 Resistance News Items...
Quality assessment program for genotypic antiretroviral testing improves detection of drug resistance mutations
Sayer DC, et al. J Clin Microbiol. 2003;41:227-236.
[http://jcm.asm.org/cgi/content/abstract/41/1/227]
Four plasma samples from HIV-1 positive, treated donors were sent to nine laboratories, three of which used commercial testing assays, and six of which used in-house assays. Because of variability in the identification of nucleotide mixtures, the authors found test results only 38% concordant at drug resistance mutation sites, demonstrating the need for ongoing quality assessment programs.
Lamivudine can exert a modest antiviral effect against human immunodeficiency virus type 1 containing the M184V mutation
Quan Y, et al. Antimicrob Agents Chemother. 2003;47:747-754.
[http://aac.asm.org/cgi/content/abstract/47/2/747]
In cells infected with HIV-1 expressing the reverse transcriptase multi-drug resistance protein M184V, the authors found that 3TC can still, by itself and in combination with other drugs, exert an inhibitory effect on reverse transcriptase activity.
Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients
Marcelin AG, et al. Antimicrob Agents Chemother. 2003;47:594-600.
[http://aac.asm.org/cgi/content/abstract/47/2/594]
In 49 PI-experienced, amprenavir-naïve HIV-1-infected patients treated with amprenavir plus ritonavir, the authors found that a genotypic inhibitory quotient incorporating the number of PI resistance mutations was a better predictor of virologic response than virologic or pharmacologic variables used alone.
Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors
Watkins T, et al. Antimicrob Agents Chemother. 2003;47:759-769.
[http://aac.asm.org/cgi/content/abstract/47/2/759]
After applying selective pressure to HIV-1 infected cells with three protease inhibitors (indinavir, ritonavir and saquinavir), the authors developed a molecular clone carrying the eight most common resistance mutations seen in the experiments. The authors demonstrated patterns of drug resistance that extend to near the limits of attainable selective pressure.
Influence of reverse transcriptase variants, drugs, and VPR on human immunodeficiency virus type 1 mutant frequencies
Mansky LM, et al. J Virol. 2003;77:2071-2080.
[http://jvi.asm.org/cgi/content/abstract/77/3/2071]
After testing a panel of HIV-1 RT variants, the authors found different mutation frequency phenotypes from various mutation combinations, and increased mutant frequencies when virus replication occurred in the presence of drugs. The authors concluded that HIV-1 mutant frequencies can change by single amino acid substitutions in RT.
Correlation of phenotypic zidovudine resistance with mutational patterns in the reverse transcriptase of human immunodeficiency virus type 1: interpretation of established mutations and characterization of new polymorphisms at codons 208, 211, and 214
Stürmer M, et al. Antimicrob Agents Chemother. 2003;47:54-61.
[http://aac.asm.org/cgi/content/abstract/47/1/54]
In 223 clinical samples with phenotypic zidovudine resistance, the authors found that 150 samples contained the M184V mutation. In addition, analysis of classical mutational patterns demonstrated increasing zidovudine resistance with increasing number of zidovudine mutations, while additional RT mutants (H208Y, R211K, L214F) further influenced ZDV resistance.
Actinomycin D induces high-level resistance to thymidine analogs in replication of human immunodeficiency virus type 1 by interfering with host cell thymidine kinase expression
Imamichi T, et al. J Virol. 2003;77:1011-1020.
[http://jvi.asm.org/cgi/content/abstract/77/2/1011]
Treatment of MT-2 cells with actinomycin D led to a high level of resistance to thymidine analogs (zidovudine, stavudine), but not to other NNRTIs, NRTIs or PIs. The authors concluded that actinomycin D causes a novel form of thymidine analog resistance by suppressing host cell thymidine kinase-1 expression.
Association between virus-specific T-cell responses and plasma viral load in human immunodeficiency virus type 1 subtype C infection
Novitsky V, et al. J Virol. 2003;77:882-890.
[http://jvi.asm.org/cgi/content/abstract/77/2/882]
In an HIV-1 subtype C consensus sequence, the authors demonstrated an important role of the Gag p24-specific immune responses in viremia control, and more rapid viral escape from immune responses to Nef with no restraint of plasma viral load.
Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy
Prabu-Jeyabalan M, et al. J Virol. 2003;77:1306-1315.
[http://jvi.asm.org/cgi/content/abstract/77/2/1306]
By studying the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease, the authors found that the V82A mutation compromises drug interactions while not greatly affecting substrate interactions.
Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C
Ball SC, et al. J Virol. 2003;77:1021-1038.
[http://jvi.asm.org/cgi/content/abstract/77/2/1021]
After comparing nine subtype B and six subtype C HIV-1 isolates added to peripheral blood mononuclear cell cultures, the authors found that subtype B and C HIV-1 may be transmitted with equal efficiency, but that subtype C isolates may be less fit following initial infection and may lead to slower disease progression.
Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors
Wang X, et al. Mol Pharmacol. 2003;63:65-72.
[http://molpharm.aspetjournals.org/cgi/content/abstract/63/1/65]
In CD4+ T cells cultured to express a high level of breast cancer resistance protein, the authors found that the cell line showed reduced intracellular accumulation and retention of doxorubicin. In addition, the cells were resistant to AZT, lamivudine and several other anti-cancer drugs. In contrast, there was no resistance found with NNRTIs and PIs.
A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors
Wainberg MA, et al. AIDS. 2003;17:F1-F5.
[http://ipsapp003.lwwonline.com/content/getfile/13/1067/1/abstract.htm]
Analyzing B and non-B clinical isolates, the authors found that when exposed to efavirenz in tissue culture, clade C isolates developed the V106M mutation, which conferred high-level cross-resistance to all NNRTIs.
A specific subtype C of human immunodeficiency virus type 1 circulates in Brazil
Soares M, et al. AIDS. 2003;17:11-21.
[http://ipsapp003.lwwonline.com/content/getfile/13/1067/4/abstract.htm]
After sequencing the protease and reverse transcriptase genomic regions of 112 HIV-1-positive subjects from Brazil, the authors found that introduction of HIV-1 subtype C in Brazil was likely a single event of one or a mixture of similarly related strains. Recombination of subtype C and B viruses is seen as an ongoing process in this country.
Past 2002 Resistance News Items...
Knowledge of genotypic resistance mutations among providers of care to patients with human immunodeficiency virus
Salama C. et al. Clin Infec Dis. 2002:36:000.
[http://www.journals.uchicago.edu/CID/journal/ issues/v36n1/020936/brief/020936.abstract.html]
Using a questionnaire to assess clinician knowledge, the authors found that only 24% of respondents could identify at least one mutation for each of at least four drug groups, while 36% could not match any mutations with any drug group. Knowledge was poorest among providers caring for up to 50 patients.
Concordant modulation of neutralization resistance and high infectivity of the primary human immunodeficiency virus type 1 MN strain and definition of a potential gp41 binding site in gp120
Leavitt M, et al. J Virol. 2003;77:560-570.
[http://jvi.asm.org/cgi/content/abstract/77/1/560]
Studying clones of the T-cell-line-adapted MN strain and the vaccine neutralization-resistant primary MN strain, the authors found that mutations in gp120 and gp41 contributed to the neutralization resistance, high-infectivity phenotype. Furthermore, these mutations depended on sequences in the leucine zipper domain of gp41.
Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication
Matsuoka-Aizawa S, et al. J Virol. 2003;77:318-327.
[http://jvi.asm.org/cgi/content/abstract/77/1/318]
After finding a unique HIV-1 variant (CL-4) that exhibited a high level of nelfinavir (NFV) resistance, the authors determined that it was the p17PR segment of CL-4 that confers the NFV-dependent replication enhancement phenotype.
HIV type 1 group M clades infecting subjects from rural villages in equatorial rain forests of Cameroon
Zhong P, et al. JAIDS. 2002;31:495-505.
[http://ipsapp003.lwwonline.com/content/getfile/1960/109/7/abstract.htm]
In a study of 49 plasma samples from rural villages across Cameroon, the authors found that 61% of HIV-1 subtype M infections were clade A or CRF02_AG-like. Overall, HIV-1 group M clades identified included A, D, F (F2), G, and H. The authors concluded that HIV-1 diversity in rural villages in the rain forest of Cameroon is at least as broad as that observed in Cameroon's major cities.
Underevaluation of HIV-1 plasma viral load by a commercially available assay in a cluster of patients infected with HIV-1 A/G circulating recombinant form (CRF02)
Amendola A, et al. JAIDS. 2002;31:488-494.
[http://ipsapp003.lwwonline.com/content/getfile/1960/109/6/abstract.htm]
The authors compared three assays (Bayer Versant; Roche Amplicor Monitor; Organon Teknika NucliSens) in their ability to detect and quantify the HIV-1 intersubtype A/G CRF02. In 114 plasma samples infected with CRF02, NucliSens showed a worse performance in detecting and quantifying viremia.
HIV-1 subtypes in Luxembourg, 1983-2000
Deroo S, et al. AIDS. 2002;16:2461-2467.
[http://ipsapp003.lwwonline.com/content/getfile/13/1066/12/abstract.htm]
According to a retrospective study of plasma samples from HIV-infected patients in Luxembourg between 1983 and 2000, the prevalence of non-B subtypes has increased ninefold since 1990. The authors found that non-B subtypes showed no decreased susceptibility to antiretroviral drugs, while a significantly higher proportion of B viruses showed resistance to a range of antiretroviral drugs.
What can modeling tell us about the threat of antiviral drug resistance?
Blower S, Volberding P. Curr Opin Infect Dis. 2002;15:609-614.
[http://ipsapp003.lwwonline.com/content/getfile/1661/18/9/abstract.htm]
Results from several studies using mathematical models predict that more widespread usage of antiretroviral therapies (ART) will inevitably lead to a high prevalence of drug-resistant HIV, while at the same time saving a substantial number of lives. The authors conclude that more clearly defined public health goals will help decide whether or not this high prevalence of HIV drug resistance is a justifiable consequence.
Early evolution of the human immunodeficiency virus type 1 subtype C epidemic in rural Malawi
McCormack GP, et al. J Virol. 2002;76:12890-12899.
[http://jvi.asm.org/cgi/content/abstract/76/24/12890]
The authors traced the evolution of HIV-1 subtypes in the central east African region of Malawi over the last 20 years. There were multiple introductions of HIV-1 subtypes A, C and D with limited spread, followed by explosive growth of a subtype C cluster, probably arising from a single introduction in or before 1983.
Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia
Shulman N, et al. Antimicrob Agents Chemother. 2002;46:3907-3916.
[http://aac.asm.org/cgi/content/abstract/46/12/3907]
In 37 HIV-infected subjects switched from a regimen of 800 mg indinavir TID to 400 mg indinavir BID plus 400 mg ritonavir BID, the authors found that the virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure, was superior to either baseline resistance or drug exposure alone in predicting virologic response.
Mutagenically separated PCR assay for rapid detection of M41L and K70R zidovudine resistance mutations in CRF01_AE (subtype E) human immunodeficiency virus type 1
Myint L, et al. Antimicrob Agents Chemother. 2002;46:3861-3868.
[http://aac.asm.org/cgi/content/abstract/46/12/3861]
In 51 HIV-1 subtype E clinical samples, a newly constructed mutagenically separated PCR (MS-PCR) assay and direct nucleotide sequencing showed concordance of 92% and 100%, respectively, in detecting zidovudine resistance mutations M41L and K70R. The authors concluded that the MS-PCR assay could be a rapid, highly sensitive tool for surveillance of drug-resistant mutations in developing countries.
Phenotypic and genotypic analysis of biologically cloned human immunodeficiency virus type 1 isolates from patients treated with zidovudine and lamivudine
Stoeckli CT, et al. Antimicrob Agents Chemother. 2002;46:4000-4003.
[http://aac.asm.org/cgi/content/abstract/46/12/4000]
The authors found that mutations at RT codons 44, 118, 207 and 208 were significantly correlated with zidovudine resistance in biologically cloned HIV-1 isolates. Sequences from other databases showed that these mutations were more common in HIV-1 isolates from patients treated with zidovudine and lamivudine than in patients not exposed to these drugs.
env chimeric virus technology for evaluating human immunodeficiency virus susceptibility to entry inhibitors
Fikkert V, et al. Antimicrob Agents Chemother. 2002;46:3954-3962.
[http://aac.asm.org/cgi/content/abstract/46/12/3954]
In delineating the phenotypic resistance and cross-resistance profiles of different clones of HIV-1 strains in the presence of the fusion inhibitor T20, the authors demonstrated the use of env chimeric virus technology (CVT) in elucidating the region important for the resistance and cross-resistance of HIV strains to entry inhibitors.
Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs
Huisman MT, et al. AIDS. 2002; 16(17):2295-2301.
[http://ipsapp003.lwwonline.com/content/getfile/13/1065/9/abstract.htm]
Out of several drug transporters of the ATP-binding cassette family, the authors found that only multidrug resistance protein 2 (MRP2) efficiently transported saquinavir, ritonavir and indinavir. This activity, which was enhanced by other drugs, may reduce HIV PI oral bioavailability.
Rapid assessment of phenotypic resistance to protease inhibitors in human immunodeficiency virus type 1 group O
Rodés B, et al. J Clin Microbiol. 2002;40:4313-4316.
[http://jcm.asm.org/cgi/content/abstract/40/11/4313]
Using a bacteriophage lambda-based method, the authors detected a 6-fold reduction in the susceptibility to indinavir and a 24-fold reduction in the susceptibility to saquinavir in a treatment-experienced patient infected with HIV-1 group O. The authors found the results concordant with those obtained by a drug susceptibility assay with primary HIV isolates.
Structure of HIV-2 reverse transcriptase at 2.35-Å resolution and the mechanism of resistance to non-nucleoside inhibitors
Ren J, et al. Proc Natl Acad Sci U S A. 2002;99:14410-14415.
[http://www.pnas.org/cgi/content/abstract/99/22/14410]
The authors report the crystal structure of HIV-2 reverse transcriptase (RT), revealing molecular details of HIV-2 RT's intrinsic resistance to NNRTIs, most notably differences compared with HIV-1 RT within the "NNRTI pocket" at conserved and nonconserved residues.
Molecular mechanisms of resistance to human immunodeficiency virus type 1 with reverse transcriptase mutations K65R and K65R+M184V and their effects on enzyme function and viral replication capacity
White KL, et al. Antimicrob Agents Chemother. 2002 Nov;46(11):3437-3446.
[http://aac.asm.org/cgi/content/abstract/46/11/3437]
The authors found that viruses containing K65R showed decreases in susceptibility to tenofovir, ddI, abacavir and the active metabolite of amdoxovir. The addition of M184V caused further decreases in susceptibility to ddI and abacavir, but increased susceptibility to tenofovir. For many of these NRTIs, the presence of K65R correlated with an increase in inhibitory capacity, but this did not hold true with the addition of M184V.
Stampidine is a potent inhibitor of zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical human immunodeficiency virus type 1 isolates with thymidine analog mutations
Uckun FM, et al. Antimicrob Agents Chemother. 2002 Nov;46(11):3613-3616.
[http://aac.asm.org/cgi/content/abstract/46/11/3613]
The authors found that stampidine, a novel aryl phosphate derivative of stavudine, inhibited each one of nine clinical HIV-1 non-subtype B isolates and 20 NRTI-resistant (genotypic and phenotypic) HIV-1 isolates.
Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients
Shulman NS et al. J AIDS. 2002; 31(2):121-127.
[http://ipsapp003.lwwonline.com/content/getfile/1960/105/1/abstract.htm]
Using a phenotypic assay, the authors found that in 240 antiretroviral-naive patients, a greater than 1.4-fold change d4T susceptibility was associated with failure to achieve significant viral load reduction after eight weeks of d4T monotherapy.
No evidence for persistence of multidrug-resistant viral strains after a 7-month treatment interruption in an HIV-1-infected individual
Walter H, et al. J AIDS. 2002; 31(2):137-146.
[http://ipsapp003.lwwonline.com/content/getfile/1960/105/3/abstract.htm]
The authors report a case study supporting treatment interruption as a strategy to overcome HIV drug resistance. The authors found that in a patient who interrupted antiretroviral treatment for seven months after 3.5 years of therapy, multidrug-resistant viruses gradually disappeared. PI resistance was completely lost, while resistance to RT inhibitors was still present when treatment was reinitiated.
The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis
Haubrich RH, et al. AIDS. 2002; 16(15):F33-F40.
[http://ipsapp003.lwwonline.com/content/getfile/13/1063/1/abstract.htm]
In 177 NNRTI-naive patients failing a stable antiretroviral regimen, 29% displayed hypersusceptibility to one or more NNRTIs after changing to a new regimen. The authors concluded that NNRTI hypersusceptibility was associated with greater reductions in HIV RNA and increases in CD4 cells.
Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates
Whitcomb JM, et al. AIDS 2002; 16(15):F41-F47.
[http://ipsapp003.lwwonline.com/content/getfile/13/1063/2/abstract.htm]
In a retrospective analysis, hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7%, 10.8% and 8.0%, respectively, of more than 17,000 plasma samples. The authors found that NNRTI hypersusceptibility was significantly more common in NRTI-experienced/NNRTI-naive patients, perhaps explaining the success of NNRTI salvage therapy in NRTI-experienced patients.
Detection of HIV-1 subtypes, recombinants, and dual infections in east Africa by a multi-region hybridization assay
Hoelscher M, et al. AIDS. 2002; 16(15):2055-2064.
[http://ipsapp003.lwwonline.com/content/getfile/13/1063/11/abstract.htm]
In a panel of 45 clinical samples from Uganda, Kenya and Tanzania, a new, multi-region hybridization assay (MHA) provided 90% sensitivity and 98% specificity for HIV-1 subtypes A, C and D. The authors concluded that the MHA may enable accurate and efficient genotyping of HIV-1 strains in East African populations.
Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults
Barbour, J.D. et al. J Virol. Nov 2002;76(21):11104-11112.
[http://jvi.asm.org/cgi/content/abstract/76/21/11104]
In 20 HIV-infected adults on a stable protease inhibitor-based regimen, the authors found that primary genotypic mutations within protease were temporally associated with increasing phenotypic resistance and decreasing replicative capacity. The authors concluded that HIV may be constrained in its ability to become both highly resistant and highly fit.
Plasma RNA viral load in human immunodeficiency virus type 2 subtype A and subtype B infections
Damond, F. et al. J Clin Microbiol. 2002 Oct;40(10):3654-3659.
[http://jcm.asm.org/cgi/content/abstract/40/10/3654]
The authors' real-time, quantitative PCR method for measuring HIV-2 RNA load demonstrated 100% sensitivity at a viral load of 250 copies/ml in patients with both subtype A and subtype B strains of HIV-2.
Discordant response to antiretroviral therapy: HIV isolation, genotypic mutations, T-cell proliferation and cytokine production d'Ettorre, G et al. AIDS. 2002;16(14):1877-1885. [http://ipsapp003.lwwonline.com/content/getfile/13/1062/4/abstract.htm]
In a study of 10 discordant HIV-positive patients, seven patients who were responding to HAART and 10 failing patients, the authors found no difference in the number of drug resistance mutations between discordant and failing patients. The authors failed to conclude that genotypic mutations are involved in the discordant antiretroviral therapy response.
Magnitude and frequency of cytotoxic T-lymphocyte responses: identification of immunodominant regions of human immunodeficiency virus type 1 subtype C
Novitsky, V et al. J Virol. Oct. 2002. 76(20):10155-10168.
[http://jvi.asm.org/cgi/content/abstract/76/20/10155]
After performing a population-based analysis of the cytotoxic T-lymphocyte responses in individuals infected with HIV-1 subtype C in Botswana, researchers identified immunodominant regions across the entire HIV-1C. The authors suggested that these regions could be used in designing an HIV vaccine candidate for the population of Southern Africa.
Insertions in the reverse transcriptase increase both drug resistance and viral fitness in a human immunodeficiency virus type 1 isolate harboring the multi-nucleoside reverse transcriptase inhibitor resistance 69 insertion complex mutation Quiñones-Mateu, ME et al. J Virol. Oct. 2002. 76(20):10546-10552.
[http://jvi.asm.org/cgi/content/abstract/76/20/10546]
The authors found that recombinant HIV-1 viruses harboring reverse transcriptase multi-NRTI resistance complexes in the presence of AZT were more fit than wild-type viruses. However, in the absence of drug, viral fitness varied between strains lacking or harboring different RT mutations. The authors suggested comparing complex mutation patterns with viral fitness to elucidate the role of uncharacterized drug resistance mutations.
Antiretroviral Drug Resistance Mutations in Antiretroviral-Naive Prisoners
Stone, DR et al. Clin Infect Dis. 2002;35:000.
[http://www.journals.uchicago.edu/CID/journal/issues/v35n7/020676/brief/020676.abstract.html]
In a cohort of 25 antiretroviral-naive, HIV-positive inmates in Massachusetts, the authors found silent mutations, unexpected mutations at resistant sites, and resistance mutations. The authors concluded that the prevalence of drug-resistance mutations among these inmates was the same as the prevalence rate recorded for non-prison populations in the same state.
The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1) Olson, DP et al. AIDS 2002; 16(13):1743-1747. [http://ipsapp003.lwwonline.com/content/getfile/13/1061/5/abstract.htm]
The authors found that ritonovir inhibited the activity of MRP-1, shown by the drug’s ability to prevent MRP-1 efflux of the anti-cancer agent etoposide. No other anti-HIV or anti-cancer drugs had an effect on MRP-1, leading the authors to suggest that ritonavir may be used as a lead compound to develop more potent MRP-1 inhibitors.
Forty-one near full-length HIV-1 sequences from Kenya reveal an epidemic of subtype A and A-containing recombinants Dowling, DE et al. AIDS 2002; 16(13):1809-1820. [http://ipsapp003.lwwonline.com/content/getfile/13/1061/15/abstract.htm]
In 41 HIV-1 positive blood samples from six hospitals across southern Kenya, the authors found that 93% of HIV-1 genomes were subtype A or A-containing recombinant strains (a select few had subtype A2). The authors recommended that vaccine candidates in Kenya should be based on subtype A strains, but testing for breakthrough infections should be able to identify non-A subtypes, the A2 sub-subtype and recombinants.
Guidelines for using antiretroviral agents among HIV-infected adults and adolescents Dybul, M et al. Ann Intern Med. 2002;137:381-433.
[http://www.annals.org/issues/v137n5s/abs/200209031-00001.html]
In an update to the Department of Health and Human Services’ 1998 HIV treatment guidelines, the authors recommended that patients should be guided by the results of drug-resistance testing, among other factors, when changing from their original regimen after treatment failure.
In vitro intersubtype recombinants of human immunodeficiency virus type 1: comparison to recent and circulating in vivo recombinant forms Quiñones-Mateu, ME et al. J Virol 2002 Oct 1;76(19):9600-9613.
[http://jvi.asm.org/cgi/content/abstract/76/19/9600]
After dually infecting human PBMCs with seven pairs of HIV-1 isolates from different subtypes (A to F), the authors found that in vitro intersubtype recombination was at least twofold more frequent in the V1-to-V3 region than in any other env fragment. The authors suggested that the generated HIV-1 recombinants may be used as a model for in vivo intersubtype recombination as well as diagnostic assays and vaccine development.
Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients Masquelier, B et al. Antimicrob Agents Chemother. 2002 Sep;46(9):2926-2932.
[http://aac.asm.org/cgi/content/abstract/46/9/2926]
In 68 French HIV-positive patients on lopinovir-ritonavir (LPV/r), the authors found that the presence of multiple protease 154V mutation at baseline, a lopinavir mutation score of >5 mutations, and a high number of previous PIs, among other factors, were independently associated with virologic failure. The authors suggested that genotypic and pharmicokinetic parameters can help optimize LPV/r therapy in PI-experienced patients.
The evidence is just not there Kirchner, JT. BMJ 2002;325(24 Aug.).
[http://bmj.com/cgi/eletters/325/7361/408/a#24932]
Despite a recent NEJMarticle reporting the rise of drug-resistance in North America, the author states that the evidence is still not strong enough to recommend resistance testing for all treatment naïve patients. In fact, for most of the 300,000 HIV-infected individuals in the U.S. who have not been tested and are not currently in care, a genotype is not going to provide useful information prior to HAART.
Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision Boyer, PL et al. J Virol 2002 Sep;76(18):9143-51.
[http://jvi.asm.org/cgi/content/abstract/76/18/9143]
To test their theory that the T215F/Y mutation makes the binding of ATP to HIV-1 RT more effective, thereby increasing the excision of AZTMP in vitro and increasing AZT resistance in vivo, the authors measured the effects of fingers insertion mutations on the misincorporation and excision of several nucleoside analogs. The authors found that the mutants with the fingers insertion and T215Y excised all of the nucleoside analogs that were tested more efficiently than wild-type RT or a mutant RT carrying the classical AZT-resistance mutations.
Combination of drugs and drug-resistant reverse transcriptase results in a multiplicative increase of human immunodeficiency virus type 1 mutant frequencies Mansky, LM et al. J Virol 2002 Sep;76(18):9253-9.
[http://jvi.asm.org/cgi/content/abstract/76/18/9253]
In a study to determine the effects of drug-resistant reverse transcriptase (RT) and antiretroviral drugs on the HIV-1 mutant frequency, the authors found a multiplicative effect with AZT-resistant or AZT/3TC dually resistant RT and several drugs (AZT, 3TC, hydroxyurea and thymidine). This effect increased the likelihood of recovering virus mutants to 20 times that encountered in the absence of drug or drug-resistant strains.
Drug resistance in AIDS AIDS News, U.S. Pharmacist 27:08
[http://www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=917]
According to reports presented at the XIV International AIDS conference, 78% of HIV-infected individuals in the U.S. are now infected with virus that has reduced susceptibility to at least one drug. Researchers called this trend a threat to recent treatment advances. In another report, investigators found that drug resistance testing of pregnant women is necessary to determine the most effective prophylactic therapy for the newborn.
Prevalence of protease and reverse transcriptase drug resistance mutations over time in drug-naïve human immunodeficiency virus type 1-positive individuals in Rio de Janeiro, Brazil Dumans, AT et al. Antimicrob Agents Chemother 2002 Sep;46(9):3075-3079.
[http://aac.asm.org/cgi/content/abstract/46/9/3075]
The authors genotypically and phenotypically evaluated 49 blood samples from drug-naïve HIV-type 1-infected blood donors living in Rio de Janeiro state, Brazil, in 1998 to determine the prevalence of mutations that confer resistance to protease inhibitors and to nucleoside and nonnucleoside reverse transcriptase inhibitors.
