K65R and Y181C are less prevalent in HAART-experienced HIV-1 subtype A patients.

The vast majority of HIV-1 infections globally are caused by subtype A or C, although little is known about their drug resistance profiles. We found that HAART-experienced patients infected with subtype A had a lower prevalence of K65R and Y181C than those with subtypes B or C, despite similar exposure to antiretroviral agents that select for these mutations. If confirmed, this information may be important in the planning of antiretroviral regimens in patients infected with HIV-1 subtype A.

Drug resistance is uncommon in pregnant women with low viral loads taking zidovudine monotherapy to prevent perinatal HIV transmission.

Zidovudine monotherapy is used to reduce perinatal HIV transmission in women with low viral loads. There are few data on the risk of drug resistance in this select cohort of women. We determined the prevalence of newly acquired mutations conferring reduced sensitivity to zidovudine after exposure during pregnancy, and found that the development of mutations was uncommon and was restricted to women treated before 1998 who had higher baseline viral loads than those currently recommended monotherapy.

Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy.

BACKGROUND: Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. METHODS: A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. RESULTS: Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01) CONCLUSIONS: This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.

Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study.

OBJECTIVE: To examine whether the level of primary resistance to HIV drugs is increasing in the United Kingdom. DESIGN: Multicentre observational study. SETTING: All virology laboratories in the United Kingdom carrying out tests for HIV resistance as part of routine clinical care. PARTICIPANTS: 2357 people infected with HIV who were tested for resistance before receiving antiretroviral therapy. MAIN OUTCOME MEASURE: Prevalence of drug resistance on basis of the Stanford genotypic interpretation system. RESULTS: Over the study period (February 1996 to May 2003), 335 (14.2%, 95% confidence interval 12.8% to 15.7%) samples had mutations that conferred resistance to one or more antiretroviral drugs (9.3% high level resistance, 5.9% medium level resistance). The prevalence of primary resistance has increased markedly over time, although patterns are specific to drug class; the largest increase was for non-nucleoside reverse transcriptase inhibitors. In 2002-3, the prevalence of resistance to any antiretroviral drug to nucleoside or nucleotide reverse transcriptase inhibitors, to non-nucleoside reverse transcriptase inhibitors, or to protease inhibitors was 19.2% (15.7% to 23.2%), 12.4% (9.5% to 15.9%), 8.1% (5.8% to 11.1%), and 6.6% (4.4% to 9.3%), respectively. The risk of primary resistance was only weakly related to most demographic and clinical factors, including ethnicity and viral subtype. CONCLUSIONS: The United Kingdom has one of the highest reported rates of primary resistance to HIV drugs worldwide. Prevalence seems still to be increasing and is high in all demographic subgroups.

Antiretroviral drug resistance among HIV-1 infected children failing treatment.

High levels of HIV-1 replication occur following perinatal infection and antiretroviral drugs may not fully suppress viral load during the early years of childhood. Adherence to treatment may also be difficult among children. These two factors will contribute to development of drug resistance but limited paediatric data are available. This study has, therefore, evaluated the prevalence of drug resistance among children and assessed the contribution of adherence to failing therapy. Samples from 26 children who had experienced virological failure to antiretroviral therapy were tested for drug resistance using the Visible Genetics TRUGENE trade mark HIV-1 genotyping assay. HIV-1 subtype was determined using a peptide-based EIA and drug adherence determined by physician assessment. Twenty-four children were black African, 23 of whom were infected with a non-B subtype. HIV RNA sequence data was obtained for 21 of the 26 children; at treatment failure resistance mutations were detected in the protease gene of 7 (33%) and the reverse transcriptase gene of 19 (90%). A lower proportion of children had evidence of drug resistance at nadir and no resistance mutations were detected prior to treatment. Genotypic resistance was common in those treated with lamivudine (10/11, 91%), nevirapine (6/8, 75%), and zidovudine (7/11, 64%). The prevalence of mutations was lower among those receiving other nucleoside reverse transcriptase inhibitors and protease inhibitors. In 50% of children, drug adherence was >90%. Antiretroviral drug resistance was common among this group of children failing therapy, the majority of whom were infected with non-B subtypes of HIV-1. As adherence to treatment was low in 50%, this was likely to be an important contributory factor.

Monitoring the progress of BK virus associated nephropathy in renal transplant recipients.

BACKGROUND: Nephropathy associated with BK virus (BKVAN) has recently emerged as an important cause of allograft failure following renal transplantation. The aim of this study was to evaluate the effectiveness of laboratory markers in the follow-up of patients with BKVAN. METHODS: Serial samples from seven renal transplant recipients with biopsy proven BKVAN were studied. The median follow-up time from diagnosis was 76 weeks. Intervention after the diagnosis of BKVAN included immunosuppression dose reduction, alternative immunosuppressive agents and/or antiviral therapy with cidofovir. Serial urine samples (n = 127) were collected for electron microscopy (EM), decoy cell detection and quantitative urine BK viral load using real-time polymerase chain reaction. Serum BK viral load was also measured serially (n = 72). RESULTS: All patients showed a reduction in serum and urine viral load during the period of follow-up co-incident with the loss of decoy cells and negative urine EM. Urine samples that were negative for decoy cells or polyomavirus by EM had a urine viral load <10(6) copies/ml and a corresponding serum viral load <10(3) copies/ml. In paired serum/urine samples, there was a proportional relationship between serum and urine viral load with each urine viral load approximately 1000-fold higher than the corresponding serum level. Serum and urine viral loads that decreased to <200 and < 10(6) copies/ml, respectively, correlated with histological improvement. CONCLUSION: Negative EM and absence of decoy cells could be used as broad indicators of a response to intervention. However, measurement of BK virus DNA level provided a wider dynamic range and could be a better choice for determining the extent of viral control.