Frankfurt resistance meeting highlights

The Second Frankfurt Symposium on the Clinical Implications of HIV Drug Resistance took place between February 25-27. The meeting was an opportunity for the European Union-sponsored Resistance Testing guidelines group to present its findings. These guidelines will be covered in more detail shortly at aidsmap.com.

Some new data was also unveiled at the meeting. Abstracts reporting on data already presented at the Seventh Retroviruses Conference (of which there were many) have not been summarised in this report.

3TC resistance delays subsequent NA resistance…or does it?

The development of 3TC resistance during first-line therapy may delay the emergence of resistance mutations associated with AZT or d4T treatment. A review of 140 patients found that prior 3TC experience was associated with a significantly lower incidence of major AZT and d4T-related mutations, and less impaired sensitivity to AZT and d4T when compared with 3TC-naïve individuals (Ait-Khaled).

On the other hand, d4T resistance may emerge if the drug is being used in combination with 3TC due to a complex of mutations conferring multi-nucleoside analogue resistance, according to Spanish researchers. Eight out of 22 patients failing on a d4T-containing regimen showed genotypic changes related to 3TC treatment; in four cases a complex of mutations at M184V/L214F and R211K had emerged. This complex is known to confer cross-class resistance to nucleoside analogues (De Mendoza).

Stone analysed the emergence of resistance mutations in 60 treatment-naive individuals who received abacavir monotherapy for up to 24 weeks at one of three doses before switching to triple therapy comprising abacavir/AZT/3TC. At 120 weeks 54% of those with abacavir-related mutations prior to intensification (baseline) still had viral load below 400 copies on an intent to treat analysis (12 discontinuations), and two distinct patterns of subsequent genotypic changes were noted. In those without baseline mutations at L74V and M184V, a change was more likely to appear at Y115F than at L74V subsequent to an initial M184V mutation.

Acquisition of drug-resistant HIV

A European review of 54 patients from Berlin found that 13% of recent seroconverters identified between 1996 and 1999 had reduced sensitivity (phenotypic resistance) to at least one drug, in most cases to the nucleoside analogues AZT or 3TC. Only one PI-resistant strain was identified, and no multi-drug resistant isolates were identified (Kucherer).

A review of 20 UK seroconverters showed that only one had evidence of acquired AZT resistance, with major reverse transcriptase mutations at T215L and M41L, whilst two others had minor mutations that may be naturally occuring changes in wild type virus (polymorphisms). The individual with major AZT resistance was identified in 1997. Seroconverters analysed numbered 7 from 1995, 8 from 1996, 3 from 1997, one from 1998 and one from 1999. Eleven out of twenty had similar protease mutations unlikely to be related to acquired drug resistance (Cane).

Salvage therapy

A review of virus isolates from 132 individuals who had failed at least one PI showed that 67% were still sensitive to amprenavir, and a further 16% exhibited a four to eight fold reduction in sensitivity. 23 out of 62 samples resistant to four PIs were still sensitive to amprenavir, and prior treatment with indinavir or ritonavir was more strongly associated with amprenavir resistance than prior saquinavir or nelfinavir treatment (Schmidt). The researchers found that amprenavir resistance was strongly predicted by a complex of mutations at 84V and/or any two of codons 46, 54 or 90.

One-quarter of a Spanish sample of 115 patients with virological rebound and multi-drug experience had significant resistance to drugs from all three classes, implying serious difficulties in salvage therapy. Samples were taken from individuals who had taken drugs from each of the classes for at least six months. After conducting genotypic tests the researchers estimated the proportions with resistance to individual drugs:

One third were resistant to AZT, 3TC, nevirapine, ritonavir and indinavir. 60% had resistance to at least one drug from one class, but 14% had no evidence of drug resistance despite extensive treatment experience, no recent drug holidays, a good record of compliance and virological rebound (Soriano).

A review of nine individuals in the Virgo study of d4T/ddI/nevirapine who experienced virological rebound found that an AZT-sparing initial regimen did not prevent the development of the K103N mutation in two-thirds of cases (Ferre).

Even when recycled d4T forms part of a failed salvage therapy regimen, there may be no detectable loss of sensitivity to the drug. Spanish researchers looked at paired isolates from 41 patients sampled at the time of virological failure of their first d4T-containing regimen and again after failure of their d4T-containing salvage regimen. At the time of first failure, 73% still had virus isolates sensitive to d4T, and after second failure only two out of thirty individuals had experienced a reduction in sensitivity. Paradoxically, three individuals experienced improvements in d4T sensitivity by the time of second failure. Genotypic changes associated with reduced d4T sensitivity were identified in two individuals at codon 69, the position associated with class-wide resistance to nucleoside analogues (Moreno).

Richard Hoetelmans reported a possible boosting effect of ritonavir or indinavir on d4T levels in plasma and cerebrospinal fluid. Individuals taking 40mg d4T bid in four studies (050, ADAM, Era and Prometheus) were assessed. In patients not receiving IDV or RTV (in the 050 and ADAM trials) d4T levels were three to six times lower than in those receiving IDV or RTV. A multivariate analysis revealed a significant relationship between use of either PI and d4T concentrations in plasma. BMI was also significantly associated with d4T levels in plasma, whilst d4T levels in the CSF were associated with use of ritonavir and the CD4 cell count at the time of sampling.

A salvage regimen of ritonavir/indinavir and an NNRTI proved moderately effective in heavily pre-treated patients, according to a Spanish research team, but almost 60% reported drug-related adverse events. Thirty-four individuals receiving RTV/IDV plus either nevirapine (n=8) or efavirenz (n=26) were analysed for viral load responses, drug levels and resistance. Twenty-four had already failed nevirapine therapy, and the group was heavily PI-experienced, with an average exposure of 3.5 PIs prior to commencing the RTV/IDV regimen. More than half (62%) experienced a viral load decline of greater than 1 log at month 3, but response was poorer in those with the V82A or L90M mutations. Surprisingly, those with isolates resistant to ritonavir, indinavir and efavirenz had a better than average virological response, with a decrease of 1.35 log after three months, and 0.8 log at six months (Moreno).

References

Ait-Khaled M et al. Lamivudine as part of a first-line antiretroviral regimen significantly delays the acquisition of mutations associated with zidovudine and stavudine. Antiviral Therapy 5: abstract 5, 2000.

Cane P et al. Detection of drug-resistance associated mutations in HIV primary infection within the UK. Antiviral Therapy 5, abstract 22, 2000.

De Mendoza C et al. Emergence of zidovudine resistance in HIV-positive patients receiving stavudine. Antiviral Therapy 5, abstract 6, 2000.

Ferre V et al. Nevirapine-resistant mutations occurring in nevirapine/stavudine/didanosine-treated patients. Antiviral Therapy 5, abstract 25, 2000.

Hoetelmans RMW et al. Increased stavudine concentrations in plasma and cerebrospinal fluid: a possible interaction with ritonavir and/or indinavir. Antiviral Therapy 5, abstract 44, 2000.

Kucherer C et al. Transmission of drug-resistant HIV-1 in recent seroconverters. Antiviral Therapy 5, abstract 7, 2000.

Moreno S et al. Lack of phenotypic resistance to stavudine in patients failing on stavudine-containing regimens. Antiviral Therapy 5, abstract 29, 2000.

Moreno S et al. Ritonavir/indinavir plus an NNRTI is effective after multiple failure: pharmacokinetic and resistance data. Antiviral Therapy 5, abstract 46, 2000.

Schmidt B et al. Cross-resistance to amprenavir in PI-treated patients. Antiviral Therapy 5, abstract 11, 2000.

Soriano V et al. Prevalence of drug-resistant HIV-1 genotypes in heavily pretreated patients with current virological failure. Antiviral Therapy, abstract 23, 2000.

Stone C et al. Long-term (84-120 weeks) virological and genotypic data following treatment with abacavir/lamivudine/zidovudine. Antiviral Therapy 5, abstract 20, 2000.