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Combination Therapy and its Failure.


written by David Katzenstein, M.D.

published on HIVresistanceWeb: September 2, 1999

Abstracts 108-118.
The overall theme of these papers, genotypic and phenotypic resistance in patients failing multidrug regimens, paints a picture of diverse mutations and variable phenotypic resistance in the setting of virologic failure. The presentations fuel the ongoing debate over the relative value of genotype and phenotype in predicting virologic responses to complex regimens in highly experienced patients. In addition, the question always remains whether evidence for reduced susceptibility readily translates into clinical success with any given drug or combination. Epidemiologic techniques are being widely applied to the prevalence and incidence of mutations and decreased susceptibility. The methodologies of clinical trials with the use of resistance as both predictors or virologic failure and an outcome of treatment in drug studies suggest that drug resistance phenotype and mutations explain a large amount of the failure of combination therapies. Several of the presentations highlighted the growing importance of complete clinical data including prior drug treatment, adherence to the currently prescribed drugs and the pharmacology of antiretroviral drugs, as single agents and in combination, to adequately assess the success of combination therapies.

Abstract 108.
Virco gained an early reputation as the most prolific global center for phenotypic, and more recently genotypic, testing. This impression is bolstered by the presentation of the Virco/VircoGen database, data on > 5,000 samples acquired in "routine clinical practice." Of course, the laboratories receiving and assaying these samples are able to come to conclusions that only reflect the samples qua samples and their data was not linked to drug therapy or patients or clinical responses. The clinical samples sent to Virco for resistance testing demonstrate the wide variation in the practice habits, diagnostic decisions and a wide range of drug resistance. In this analysis, they focus on the variation in phenotypic resistance within classes of drugs. Using phenotypic, recombinant virus assays, from 3 to 15% of viruses that are highly resistant with well described resistance mutations to at least one member of a class of drugs may retain susceptibility to one or more drugs within a class. They raise critical questions about in vitro cross resistance among NNRTIs and protease inhibitors, and ultimately their use, as guided by phenotypic assays. First, in NNRTI resistant viruses (see Sharon Kemp's presentation #26) Dr. Hertogs selected all samples that were, for example, considered resistant to Nevirapine and provided the percentages of those viruses that retained susceptibility (using a Virco cut-off) to one (18%) or two (3%) additional NNRTI drugs. This suggests that, at least in vitro, there may not be "absolute cross resistance" among the three NNRTIs. While the methods for genotype and phenotype may be accurate, this finding raises important questions about the use of phenotype, and particularly the "cut-offs" and their applicability in assessing reduced susceptibility. A similar resistance survey of protease inhibitors also demonstrates variation in cross resistance within the class. Here the most controversial finding is the retention of Saquinavir susceptibility in 14% of the isolates, despite resistance to NFV, RTV and IDV (see abstract 68, Zolopa ). The Virco database is an invaluable source of genotype and phenotypic cross resistance. The bottom line from Dr. Hertogs' presentation was that neither phenotype, nor genotype was absolutely predictive of reduced susceptibility to other drugs within a class. However, the overall results confirm that in clinical samples sent for resistance testing there are very high levels of cross-resistance within classes.

Abstract 110.
Lee Batcheler presented the continuing genotypic and phenotypic story of NNRTI resistance in the Sustiva expanded access program. Here the data from 41 NNRTI (nevirapine or delavirdine or both) experienced patients provided with Sustiva as part of the expanded access program demonstrates the complexity of NNRTI cross resistance. The most striking findings were, as previously reported, the high frequency of the K103N mutation associated with failure. Interestingly, the observation that many of the "non-responders" added double, triple and even quadruple NNRTI mutations suggests that there is continued selective pressure from efavirenz despite the presence of baseline resistance mutations. Because patients were often treated with multiple new and recycled protease inhibitors and nucleoside reverse transcriptase inhibitors, the overall response rates, presented as virologic success or failure reflect the activity of many of the drugs. The clear message as in the Virco presentation was the importance and complexity of NNRTI mutations at 98, 100, 101, 103, 108, 181, 188 and 190 in the response to efavirenz containing regimens.

Abstract 112.
Scott Wegner presented a conceptual modeling of population pharmacokinetics that is in progress to combine pharmacologic and virologic monitoring. This touches on many of the same issues as in the VIRADAPT study. This abstract adds the technologic feat of measuring drug levels to all 14 agents from a single 100 ml aliquot of plasma. The results presented for three protease inhibitors provide evidence that population PK models will predict inadequate PI trough levels. These may be one of the many causes of increased resistance as well as drug failure.

Abstract 113.
In her description of 13 patients with multiple drug failure, treated with 8-9 drugs, Dr. Katlama points out both the hazards and potential benefits of aggressive polypharmacy. First 7/13 of the subjects withdrew before 12 weeks because of intolerance (5) or severe opportunistic infection (2). Among those able to take the 8-9 drugs there was a steady decrease in median virus load. However, there was no evidence presented that any of the subjects obtained a sustained decrease in virus load below levels of detection, which might be necessary for the use of GIGAHAART as induction therapy to a safer and more effective maintenance regimen.

Abstract 114.
This is a clinically based reprise of the NNRTI cross-resistance conundrum in patients treated with nevirapine and PI drugs. All were extensively NRTI and PI experienced and their "baseline" phenotypes echoed the growing observations of NNRTI resistance. Nearly 30% had either intermediate (22%) or resistant (8%) virus in recombinant assays testing nevirapine or delavirdine, and 9% showed decreased susceptibility to efavirenz. Following the failure of a nevirapine +PI regimen, phenotypic resistance increased in the 39 (50%) of patients who did not achieve < 200 copies/ml. As in Dr. Hertogs' initial presentation, genotyping in these patients demonstrated that susceptibility to efavirenz was retained in more than a third of those isolates with only a Y181C mutation and 12% of K103N bearing isolates were considered "susceptible" while all of the viruses with both K103N and Y181C demonstrated high level resistance. These findings provide support for the observation that some NNRTI experienced patients may experience beneficial transitory virologic effects from a second or third NNRTI, but this is unlikely to be sustained.

Abstracts 115 and 118.
These two presentations focused on the evolution of genotypic changes in the RT gene among patients treated with d4T(stavudine) with or without ddI (didanosine). Lisa Ross presented results from adult and pediatric populations where the use of d4T for more than a year resulted in the emergence of "zidovudine ­like mutations" most commonly 215. Similar findings were presented in somewhat greater detail by the French group, which examined dual nucleoside therapy with d4T and ddI using both a phenotypic and genotypic approach. Continuing the theme of within and cross-class resistance, they noted that a few of the isolates obtained from d4T/ddI treated subjects developed resistance to abacavir, lamivudine, or zidovudine in addition to stavudine and didanosine. More puzzling was the note that two of their nucleoside treated patients developed nevirapine resistance.




References

  1. A comparison of phenotypic, genotypic and clinical/treatment history predictors of virological response to saquinavir/ritonavir salvage therapy in a clinic-based cohort.  K Hertogs, V De Vroey, C Van den Eynde; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 108


  2. Common, rare and new genotypic and/or phenotypic HIV-1 resistance profiles observed in routine clinical practice: a survey of over 5000 isolates.  AR Zolopa, K Hertogs, R Shafer, P Dehertogh, V De Vroey, B Efron, S Bloor and B Larder; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 68


  3. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomized controlled trial .  Durant J; Clevenbergh P; Halfon P; Delgiudice P; Porsin S; Simonet P; Montagne N; Boucher CA; Schapiro JM; Dellamonica P; Department of Infectious Diseases, Archet Hospital, Nice, France.; Lancet. 1999 Jun 26;353(9171):2195-9.


  4. Relevance of protease inhibitor plasma levels in patients treated with genotypic adapted therapy: pharmacological data from the Viradapt study.  R Garraffo, J Durant, P Clevenbergh; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 109


  5. Efavirenz response in non-nucleoside reverse transcriptase inhibitor-experienced patients: results from the Sustiva Expanded Access Program.  LT Bacheler, D Baker, M Paul; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 110


  6. The development and trafficking of multidrug resistant HIV in plasma and central nervous system during the failure of combination antiviral therapy.  JK Wong, HF Günthard, RE Ellis; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 111


  7. The potential role of resistance testing and therapeutic drug monitoring in the optimization of antiretroviral drug therapy.  S Wegner, K Groen, N Aronson; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 112


  8. GIGHAART: a rescue therapy for HIV patients with multiple HAART failures.  C Katlama, C Duvuvier, M Mouroux; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 113


  9. Rate of non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen.  JL Casado, K Hertogs, L Ruiz; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 114


  10. Stavudine-based combination and monotherapy selects for zidovudine resistance HIV-1 mutations in zidovudine-naïve adults and in paediatric patients.  L Ross, S Danehower, M Johnson; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 115


  11. Selection of HIV-1 variants with wide cross-resistance to reverse transcriptase inhibitors during low-level escape to first-line dual nucleoside therapy.  E Race, F Ferchal, E Dam; Antiviral Therapy 1999; 4 (Supplement 1): Abstract 118


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