Other news from 10th BHIVA conference

Simon Collins, HIV i-Base

Atazanavir switch appears tolerable and effective

Clinical results were presented on patients who had switched to atazanavir (ATZ) on the named patient/early access programme at Brighton, East Sussex and St Mary’s Hospital, London. Limited data – largely relating to toxicity and viral load response – can be collected from these programmes. However, these results can give some support when considering a switch to this newly available once-daily protease inhibitor (PI) in situations not covered by the registrational studies.

Results were presented on 76 patients who received ATZ for a median of 15 weeks (range 1–47). The median time on antiretroviral therapy was approximately five years and the duration of prior PI therapy almost two years. Reasons for starting ATV included pill burden (20), once-daily therapy (21), adherence issues (9), hyperlipidaemia (20), gastrointestinal disturbance (11), lipodystrophy (6) and virological failure (13). Two patients died (unrelated to ATV); six stopped ATV because of patient choice (3), hypersensitivity (1) jaundice (1) and myositis (1). One patient was lost to follow-up.

Of the 28 patients who switched to ATZ with a viral load of <50 copies/ml, 27 remained undetectable. Of the 44 starting with detectable viraemia, 22 are now undetectable and the remaining 16 on therapy have experienced significant viral load reductions.

Hyperbilirubinaemia occurred in 64%, resolving in 61%; three patients experienced clinical jaundice. Hyperlipidaemia improved in 61%, with 38% of these patients able to stop lipid-lowering agents. Improvements in gastrointestinal symptoms occurred in 54%.

Ref: McDonald C, Mackie N, Smyth C et al. Clinical experience of atazanavir: tolerable and effective. Oral Abstract O2.

Therapeutic drug levels can continue three weeks after stopping efavirenz

The STOP study received an oral presentation at this year’s Retrovirus conference and is covered in detail in the April issue of HTB (Vol 5, No 3), but has particularly important implications for treatment in the UK.

Ten patients who were discontinuing or switching efavirenz, largely due to toxicity, had plasma drug levels measured weekly, while continuing on background or switched treatment, in order to collect detailed data relating to efavirenz clearance.

Efavirenz clearance was within the expected range for five patients (half-live ~50 hours), but five had efavirenz half-life >100 hours (median 123, range 114-229). Four of these were black African women who at baseline had efavirenz levels ~10,000 ng/ml (10-fold higher than minimum target) perhaps explaining the need to change for toxicity. Three women maintained therapeutic levels >1000 ng/ml 2 weeks after stopping EFV.

Current guidelines (BHIVA, 2003) suggest EFV can be stopped 7 days before shorter-acting nucleoside but these extended PK data suggest the stop window should be increased to 2–3 weeks for some patients (or efavirenz switched to nelfinavir or other shorter lasting drug for the last 3 weeks).

Ref: Taylor S, Allen S, Smit E et al. The Stop Study: after discontinuation of efavirenz (EFV), plasma concentrations can persist for >2 weeks. Oral abstract O6.

Use of detuned HIV test to establish recent infection

Accurately identifying recent HIV infection provides the opportunity to track more accurately the rate that HIV progresses in any individual. In addition to allowing entry into primary infection studies, it will also impact on the importance of earlier treatment. Anecdotally, many patients appear to progress to requiring treatment far earlier than the previous estimate of 5-8 years, and data in this area would also help address whether this is occurring.

STARHS (Serologic Testing Algorithm for Recent HIV Seroconversion) can diagnose infection within the previous 4–6 months in people who have tested HIV-positive with the routine EIA antibody test but who have not produced sufficient antibodies for this less sensitive (detuned) EIA test. Martin Fisher and colleagues reported on use of this simple test at Brighton Hospital.

Incident cases from 1996 to 2002 were determined by conventional methods (HIV-negative test within 18 months, evolving antibody response or incomplete Western blot), by STARHS and by both methods combined.

Of 486 individuals newly diagnosed during the study period 387 (89%) underwent STARHS serum analysis. New diagnoses identified as incident by conventional methods increased from 0/50 (1996) to 18/82 (2002). STARHS identified a further 48 incident infections (11% of total new infections; 48% of total incident), ranging from 2/50 (1997) to 14/82 (2002). Using a combination of conventional methods and STARHS, RHI increased over time from 9/50 (1996) to 32/82 (2002) [P<0.001].

This test is available free from the Health Protection Agency laboratory in Colindale (formerly PHLS) on 020 8200 4400 x 4262. It is not available as an initial HIV diagnostic test but only to gauge recent infection in a patient with a confirmed HIV diagnosis. There are also limitations, including only being validated for subtype-B infection. The test cannot be used for patients who have already started antiretroviral treatment or who are diagnosed with ongoing AIDS-related illnesses. The 6-month window period used in STARHS analyses for calculating population-based HIV incidence is the mean for a tested population. Although individual results would be distributed on either side of the mean and this window may not always be applicable for every individual infection, it is routinely used when accessing recent infections for individuals entering trials of primary HIV infection.

Ref: Fisher M, Dean G, Cooper V et al. Adjunctive use of the Serological Testing Algorithm for HIV Seroconversion (STARHS) identifies a high and increasing proportion of newly diagnosed infections as incident. Oral abstract O8.

Tenofovir for treatment of HBV in coinfected patients

Gilleece and colleagues from the Chelsea and Westminster Hospital presented results from an open-label study of 40 HIV/HBV coinfected patients (39 men, 1 woman) using tenofovir 245mg as part of or in addition to their antiretroviral therapy.

31 patients were 3TC-experienced, with a median exposure of 72 weeks (range 6–270). 60% of those who underwent HBV DNA polymerase sequencing had a mutation in the YMDD motif.

The median HBV viral load fell from 250 x 106 to <10,000 copies/ml at 96 weeks. 25/40 (63%) had an undetectable HBV by 48 weeks. 14/14 (100%) who reached 96 weeks had an undetectable HBV DNA level. Eight individuals became HBeAg-negative between 36 and 96 weeks, and six seroconverted to HbeAb-positive. Three of these six had lamivudine resistant mutations at baseline. All eight individuals remained HbsAg-positive.

The median CD4 count rose from 271 (baseline) to 386 (48 weeks) and 488 cells/mm3 at 96 weeks. Similarly, the CD4% rose from baseline to 96 weeks (19.2% to 24% to 22.5%).

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Several previous reports have highlighted the activity of tenofovir against HBV. [2, 3, 4] It is not clear whether any of those patients show a viral non-response as reported from adefovir where 15-20% show an HBV-RNA decrease of < 1 log (Van Bömmel, AASLD 2003).

It was also unclear whether there was any viral load rebound suggesting development of resistance.

References:

1. Gilleece Y, Nelson MR, Clarke A et al. Tenofovir in the treatment of hepatitis B (HBV)/HIV co-infected individuals. Oral abstract O19.

2. Dore GJ, Cooper DA, Pozniak, AL, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189:1185-1192.

3. Benhamou Y, Katlama C, Rozembaum W, et al. Efficacy of tenofovir disoproxil fumarate (TDF) for hepatitis B virus (HBV) in human immunodeficiency virus (HIV) infected patients. Hepatology. 2003;38(suppl 1):712A. 54th AASLD, 2003. Abstract 1155.

4. Efficacy of Tenofovir Disoproxil Fumarate in Hepatitis B Virus in HIV-co-infected Patients: The TECOVIR Study. 11th CROI, Feb 2004, San Francisco.

Sub-type-B infection in UK traced to 1975-1982

Hue and colleagues from Oxford University and University College London reconstructed a phylogenetic tree including 1784 pol gene sequences from subtype B viruses throughout the world, together with more than 1645 sequences from UK isolates, in order to identify independent introductions of HIV-1 within the UK.

Using a coalescent-based approach, incorporating a calculated rate of nucleotide substitution of the subtype B pol gene they identified four large viral lineages, indicating multiple, independent introductions of subtype B HIV-1 into the UK, dated to the period 1975–1982. Each strain showed an initial exponential phase of growth from time of introduction until the late 1980s, after which the effective population size appeared to plateau until the present, possibly due to altered sexual behaviour.

Apart from seroconversion symptoms or cases of rapid HIV progression, HIV is generally reported as taking 5-8 years to progress to clinical symptoms. An idea of the history of HIV in the UK is important for many HIV-positive people who are long-term diagnosed. It is also helpful to remember that many people were infected long before there was any knowledge of HIV as a new virus and that infection predated the availability of the first HIV test in 1985 by many years.

Ref: Hue S, Pybus OP, Pillay D. Use of coalescence theory to estimate time of introduction of HIV-1 strains into the UK, and subsequent population growth dynamics. Oral abstract O11.

HIV still missed by GPs

Gilbert and colleagues from the Health Protection Agency reported on UK nationals who have a low or unacknowledged risk of HIV and present late in the course of HIV infection, often after frequent attendances to general practitioners (GPs).

Information from 286 in-depth interviews with low or unacknowledged risk individuals and those diagnosed because of HIV-related symptoms (n=157, 55%) was compared with data about people diagnosed for other reasons.

A greater proportion of those diagnosed late were male and older, or in a long-standing relationship.

Of the 157 late diagnoses, 95 were considered to have acquired HIV heterosexually, 74 in the UK and 21 abroad, 16 through ‘high-risk’ behaviours, 16 heterosexually by a ‘high-risk’ partner and the remainder through an unusual, other or unknown route. No partners had informed them of their HIV status.

Greater awareness by GPs of common symptoms indicative of immune suppression could result in avoidable morbidity and premature mortality. The study also concluded that sensitive partner-notification practices that enable a greater number of individuals to inform their partners should be explored.

Reference:

Gilbart VL et al, CDC HPA London.Late diagnosis of HIV infection among individuals with low or unacknowledged risks in England, Wales and Northern Ireland. Oral abstract O15.