HIV Treatment Bulletin - August / September 2003
Reports by Simon Collins, Polly Clayden, Graham McKerrow and Steve Taylor for HIV i-Base

Probably the most useful insights into the importance of future clinical developments come from the annual Resistance Workshop, restricted to around 150 researchers and this year only one HIV-positive community place. So while we’d like to bring you an in-depth report from the meeting, we will have instead to report from the abstracts.

These are now available online at:

http://www.mediscover.net/journals.cfm

The abstract book repays reading, and although some of these studies were subsequently presented at the IAS meeting in Paris, among the technical presentations often focusing on the minutiae of resistance were many studies that included findings that impact directly on clinical care.

These included:

• Increases in transmission of drug resistant virus – which was detected in 11% of cases of primary infection in Europe (abstract 117) and in 17% of drug naïve individuals in the UK (abstract 124);
• Further discussion about coinfection and superinfection - data revealed that with coinfection, both viruses were likely to remain present over time, whereas in superinfection the new and fitter virus often outgrows the first (abstracts 62, 63);
• Much higher rates or nevirapine resistance than previously reported from single-dose nevirapine used to prevent mother-to-child transmission, were found by looking at earlier samples and minority viral populations - at least 75% of women showed evidence of resistance to nevirapine two weeks after a single-dose during pregnancy (abstracts 78, 79);
• Transmission of drug resistant virus does not readily revert to wild-type even in the absence of drug, and does not appear to carry substantial reduced replicative capacity (abstracts 80, 115);
• Currently available commercial resistance assays are insufficiently sensitive to detect low level resistance and minority populations (abstract 86, and 134, 143);
• Cross resistance between nevirapine and efavirenz can occur even in the absence of detection of key genotypic mutations detectable by population sequencing (abstracts 134, 143);
• Some drugs continue to contribute an antiviral effect, even in the presence of mutations (d4T – abstract 133, and 3TC – abstract 140);
• Replicative capacity results may be distorted by the presence of even low levels of wild-type virus in the assay (abstract 85);
• The choice of concomitant nucleosides and particularly thymidine analogue in tenofovir-including regimens may protect against MDR K65R mutation (abstracts 135, 136, 137) and possible CD8 mediated responses to tenofovir resistance from a macaques study (abstract 70). Other TDF related abstracts include 29, 30, 33, and 34;
• Indication that diversity in responses to controlling viraemia following treatment interruption (in the SSITT trial) can be explained by differences in virus, rather than host immune response (abstract 56);
• Analysis of residual viral replication below 50 copies – and the suggestion that resistance doesn’t generally occur < 50 copies due to only localised immune responses and fails to generate HIV-specific memory cells which are required to generate new resistant variants within the memory pool (abstract 57);
• Frequent discordant resistance profiles between plasma and the genital tract, with nucleoside-associated mutations (to AZT and 3TC) maintained in the vaginal tract up to four years after discontinuing those treatments (abstract 68). A second study showed transmission of and maintenance of AZT resistant virus on the male genital tract (abstract 83);
• Immunological benefit of T-20 despite resistance and shift to NSI CCDR5 virus (abstract 72).

Short reports follow for each of these subjects. Unless stated otherwise, all abstracts in the references refer to the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003 and are published as part of Antiviral Therapy Volume 8 Issue 3.

Transmission of drug resistance – at 11% in Europe and 17% in the UK

Confirmation of the increase in transmission of drug resistance was presented in several studies, and in pooled results in one large European study. The CATCH study (Combined Analysis of resistance Transmission over time of Chronically and acute HIV-infected patients in Europe) whose title doesn’t exactly trip off the tongue provided evidence of an alarmingly high rate of transmission of drug resistance in Europe.

Wensing and colleagues presented results from an analysis of more than 1,400 baseline genotypic samples collected between 1996 and 2002 in 16 countries.

Reverse transcriptase (RT) and protease (PI) sequences were received from the following countries: Austria (60), Belgium (61), Denmark (132), Finland (8), Germany (62), Greece (40), Israel (104), Italy (296), Luxembourg (163), the Netherlands (25), Norway (23), Poland (35), Portugal (124), Serbia-Montenegro (10), Spain (23) and Switzerland (262). Mutations conferring resistance to nucleosides were seen in 6.9% of isolates, resistance to NNRTIs in 2.6% of cases and to PIs in 2.2%. Multi-drug resistant virus was observed in 1.7% of subjects.

Population characteristics were available for 975 samples, and primary drug mutations associated with protease inhibitors and reverse transcriptase were detected in 11% and 9% respectively from these treatment naïve individuals. Primary mutations were detected in 11% (63/596) of seroconverters (infected <1 year) and 8% (30/379) of those with chronic infection. Thirty-one percent of the sequences were classified as non-B and in all countries except Israel, resistance was higher in subtype B sequences than non-B (12% versus 5%).

The UK appears to have higher levels than shown in this European study: the British picture was detailed in an abstract by Deenan Pillay on behalf of the UK HIV Drug Resistance Database – a collaboration between virology laboratories and major clinical centres to pool resistance data in the UK.

Firstly reporting on treatment experienced patients, just over 9,800 test results from around 7,000 patients were available from 1996 to March 2003, and the results were divided into three time periods: 1996-1998, 1999-2000 and 2001-2003. As resistance testing in widely used in early treatment failure, it is not unexpected that around 70% of samples in each period from treatment experienced patients showed at least one key RTI mutation. PI resistance in this group was detected in 26, 32 and 27% of the samples in each period and NNRTI resistance is still increasing in prevalence at 20, 40 and 48% of experienced patients over time – reflecting the prescribing practice for NNRTI first-line therapy in the UK.

Key resistance mutations in treatment naïve individuals (to compare to the CATCH study) were detected in 10, 16 and 17% of samples for the 1998-1999, 1999-2001 and 2001-2003 periods respectively.

Comment

These data support the decision in the BHIVA Treatment Guidelines to now recommend baseline resistance testing in the UK for all newly diagnosed individuals, even when immediate treatment is not being considered.

UK guidelines also now recommend resistance testing for chronically infected patients prior to initiation of therapy due to this increasing prevalence and the low cost.

With the high rate of transmitted drug resistance now in circulation this would seem entirely prudent. For those citing cost as an obstacle, deferral of commencement of treatment for just one month will cover the cost of assay.

References:

1. Wensing AMJ et al - Prevalence of transmitted drug resistance in Europe is largely influenced by the presence of non-B sequences: analysis of 1400 patients from 16 countries: the CATCH-Study. Antiviral Therapy 2003; 8:S131 (Abstract 117).

2. Pillay D, Green H et al – The UK HIV Drug Resistance Database: development and use for national surveillance. Antiviral Therapy 2003; 8:S138 (Abstract 124).

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