Is there anything left to learn? A report on the Fifth International Workshop on HIV Drug Resistance

Abstract

Although insight into the viral dynamics of human immunodeficiency virus (HIV) infection has increased dramatically over the past year, there remains much to learn in the field of antiretroviral drug resistance. Transmission of isolates with primary drug resistance is increasingly recognized. With respect to reverse transcriptase inhibitors, it appears that the use of drugs in combination may forestall the development of resistance once therapy has been initiated. Further, certain findings, particularly with respect to zidovudine and lamivudine, suggest that emergence of resistance to one agent may lead to increased susceptibility to another. These data may allow evaluation of innovative treatment strategies to avoid the development of multidrug resistance, which has now been reported in a number of settings. Protease inhibitors (PIs) are, on an individual basis, the most potent antiretroviral compounds available today. A number of studies have shown that resistance to these agents develops after the accumulation of several mutations in the protease gene of HIV. As with reverse transcriptase inhibitors, the use of PIs in the context of regimens designed to suppress viral replication as much as possible appears to forestall, perhaps indefinitely, the development of drug resistance. Although different patterns of resistance mutations have been described for the different PIs available, the issue of cross-resistance remains unresolved. For the time being, it may be best to consider all PIs as a single agent that must always be used in a regimen designed to maximally suppress viral load. In conclusion, research in the field of antiretroviral drug resistance has never been more active and productive. It is hoped that such research will lead to the development of an integrated model of the clinical and laboratory management of HIV-infected individuals. Key Words: Antiretroviral therapy, Drug resistance, Human immunodeficiency virus Nous reste-t-il quelque chose à apprendre ? Un rapport sur le cinquième Atelier international sur la pharmacorésistance du VIH RÉSUMÉ : Bien que la compréhension de la dynamique virale de l'infection au virus de l'immunodéficience humaine ait considérablement évolué au cours de la dernière année, de nombreuses lacunes restent à combler dans le domaine de la pharmacorésistance aux agents antirétroviraux. La transmission d'isolats présentant une pharmacorésistance primaire est de plus en plus reconnue. En ce qui concerne les inhibiteurs de la transcriptase inverse, il semble que l'utilisation d'une combinaison de médicaments peut prévenir le développement d'une résistance une fois que le traitement a débuté. De plus, certains résultats, en particulier ceux concernant la zidovudine et la lamivudine, permettent de croire que l'émergence d'une résistance à un médicament peut entraîner une augmentation de la sensibilité à un autre agent. Ces données pourraient O ver the past two years, researchers have become aware that the phase of clinical latency of human immunodeficiency virus (HIV) infection is not accompanied by an arrest of viral turnover. In fact, over 10 10 new virions are produced every day (1). These data have been further refined, using mathematical models that show that the half-life of plasma virions is 6 h and the average HIV generation time (from release of a virion from a cell in the circulation to its subsequent release from the next cell it infects) is just over two days (2). Given these dynamics, it is not surprising that plasma viral load decreases very rapidly once appropriate antiretroviral therapy is initiated. This is particularly true if highly effective antiretroviral drug combinations are used, whether these include protease inhibitors (PIs) (3) or non-nucleoside reverse transcriptase inhibitors NNRTIs (4). In many cases, viral load is suppressed to such an extent that the possibility of eventual eradication of HIV from the body is being suggested (5). It has now clearly been shown that the risk of long term disease progression is directly related to the baseline plasma viral load, even in patients with high CD4 cell counts at the time of their initial evaluation (6). It has also been shown that treatment-induced changes in plasma RNA levels, taken together with CD4 cell counts, are valid predictors of the clinical progression of HIV-related disease (7). Analysis of the large American AIDS Clinical Trials Group (ACTG) 175 trial suggests that, as a single marker, baseline viral load may be the most relevant predictor of ultimate response to nucleoside analogue therapy (8). Further, the magnitude of decrease in viral load is the best predictor of the clinical efficacy of the antiretroviral agents. With all of this information in mind, it has been suggested that plasma HIV RNA levels be used routinely in clinical practice (9). It is widely held that this approach would improve the care of the HIV-infected patient. ANTIRETROVIRAL RESISTANCE Resistance of clinical HIV isolates to antiretroviral compounds was first described in 1989 (10). A number of studies have suggested that drug resistance is of clinical relevance (11,12) and needs to be considered in any complete virological model of HIV disease. Since 1992, a group of international researchers has met every year to consider the issue and significance of drug resistance. The 1996 meeting, held in conjunction with the XIth International Conference on AIDS, was particularly timely, in light of the renewed emphasis on the use of clinical laboratory measures for individual patient management. As the meeting progressed, it became apparent that, although insight into the significance of viral load has increased dramatically over the past years, there remains much to learn in the field of antiretroviral drug resistance. REVERSE TRANSCRIPTASE INHIBITORS Large American and European trials, which have allowed researchers to appreciate the clinical significance of plasma viral load levels, have also allowed researchers to evaluate the potential significance of antiretroviral drug resistance, most notably to zidovudine (ZDV). At the meeting, reports of both the Delta (Europe/Australia) and ACTG 175 (USA) studies were presented. In both studies, patients received one or more of ZDV, didanosine (ddI) or zalcitabine (ddC). Interestingly, resistance to ddI and ddC was uncommon, even in patients on long term therapy. Of 220 Delta study patients, only 10 were found to have ZDV-resistant isolates (carrying previously described mutations at codons 70 and/or 215 of the reverse transcriptase gene). More complete clinical correlation was established in a group of 89 patients enrolled in ACTG 175. After 56 weeks on ZDV, patients with drug-resistant isolates had experienced a median decline in CD4 counts of 100 cells/µL and an increase in viral load of 0.5 log 10 copies/mL plasma. Patients with wild type isolates had a rise of 17 cells/µL and a decline of 0.4 log 10 copies/mL. Although the differences between the groups are relatively unimpressive, they do suggest clinical consequences of drug resistance. In this context, the possibility of transmission of strains with primary drug resistance is of some concern. In a Swiss cohort of primary HIV infection, nine of 124 patients were found to carry such strains resistant to ZDV. A similar proportion was reported in a Dutch cohort (four of 35), with three of four having been transmitted in the previous year. In Canada, a cross-sectional study of 91 infected children failed to reveal the existence of similar strains, but active ongoing surveillance is required to monitor trends in this field. Beginning in 1995, the combination of ZDV and lamivudine (3TC) has been widely used in clinical practice. In early studies of 3TC monotherapy, resistance was found to emerge quite readily. Data on the emergence of drug resistance in long term ZDV/3TC combination therapy are now available. NUCA 3001 was a controlled, randomized multicentre study of ZDV versus 3TC versus ZDV/3TC in previously untreated patients. ZDV resistance mutations were identified in eight of 12 paCan J Infect Dis Vol 9 No 3 May/June 1998 173 Report on the Fifth International Workshop of HIV Drug Resistance permettre d'évaluer des stratégies de traitement innovatrices pour éviter le développement d'une multirésistance médicamenteuse, désormais signalée dans un certain nombre d'endroits. Les inhibiteurs de la protéase sont, actuellement, sur une base individuelle, les composés antirétroviraux les plus puissants. Plusieurs études ont démontré que la résistance à ces agents survient après l'accumulation de plusieurs mutations dans le gène de la protéase du VIH. Pareil aux inhibiteurs de la transcriptase inverse, l'utilisation des inhibiteurs de la protéase, dans le cadre de régimes conçus pour supprimer au maximum la réplication virale, semble prévenir, peut-être indéfiniment, l'apparition d'une pharmacorésistance. Bien que différents schémas de mutations causant une résistance aient été décrits concernant les différents inhibiteurs de la protéase actuels, la question d'une résistance croisée reste sans réponse. Actuellement, il est préférable d'envisager tous les inhibiteurs de la protéase qui sont disponibles comme agent unique devant toujours être utilisé dans un régime visant à supprimer au maximum la charge virale. En conclusion, les recherches dans le domaine de la pharmacorésistance aux antirétroviraux n'ont jamais été aussi actives et productives. On espère que de telles recherches conduiront à la mise au point d'un modèle intégré de la prise en charge clinique et en laboratoire des individus infectés par le VIH