Study of the impact of HIV genotypic drug resistance testing on therapy efficacy.

During recent years significant progress has been made in the treatment of HIV-1, at least in part due to the availability of potent antiretroviral drugs. The goal of the current treatment strategies is to inhibit the viral replication as completely as possible by using a combination of 3 or more antiretroviral drugs. This Highly Active Antiretroviral Therapy (HAART) has radically changed the clinical outcome of HIV, leading to decreased mortality and morbidity, at least in developed countries. Additionally to the advent of new and potent drugs, demonstrations of the prognostic value of the CD4 cell count and the plasma viral load were of major importance in the development of therapeutic strategies. Especially the ability of viral load assays to assess accurately the true level of viral replication, led to a better understanding of the pathogenesis of the disease. HIV proved to be a highly dynamic infection even during the period of clinical latency. The initial enthusiasm that HAART could radically change the outcome of HIV was cooled off in face of the difficulties in real life associated with the complex treatment strategies. Besides long-term side effects and suboptimal drug potency, the emergence of resistant virus and the necessity of perfect therapy adherence are major concerns for obtaining a sustained control of viral replication. In this study we focused on HIV resistance, which remains one of the major threats for a sustained response to antiretroviral therapy. HIV proved to be able to develop resistance to all currently used antiretroviral drugs. The high replication rate of the virus together with the low fidelity of the viral reverse transcriptase, from the basis for the presence of enormous amounts of viral variants. Whenever viral replication is ongoing in the presence of antiretroviral drugs, these variants that escape the inhibitory effects of the drugs will be selected. Although the knowledge in the field of HIV resistance has expanded enormously, many issues need to be answered. Genotypic and phenotypic resistance patterns are evolving continuously, due to changes in the treatment strategies. Moreover the relation between drug resistance and therapy failure needs further investigation, in order to prove the relevance of performing resistance testing in the follow-up of HIV-infected patients. The wide availability of antiretroviral drugs has led to the transmission of resistant HIV. Infection with HIV resistant to one or more antiretroviral drugs has been observed to occur through the different transmission routes. In a first study we assessed the prevalence of genotypic resistance to antiretroviral drugs in Belgian antiretroviral-naïve HIV-infected patients. We observed that HIV strains with resistance-related mutations to one or more classes of antiretroviral drugs are not uncommon in the Belgian naïve patients. Furthermore the inclusion of samples from patients visiting the Belgian hospitals for the first time in 1995, 1997 and 1998, showed that the overall prevalence of baseline genotypic resistance remains rather constant (26-30%). The increasing trend in genotypic baseline resistance to 3TC (2% to 6.3%) and PIs (4.4% to 9.9%) as well as the decrease in ZDV-resistance (13.3% to 5.4%), reflect the change in treatment strategies, and resistance to these drugs is most probably caused by transmission of variants with resistance mutations selected during therapy. The presence of NNRTI-related mutations (around 16%) is likely to reflect the occurrence of baseline polymorphisms, since NNRTI-related mutations can occur without a replication deficit for the virus. Moreover, despite the rather recent introduction of NNRTIs into the clinic from 1997 onwards, no clear trend in NNRTI baseline resistance over time is observed. The best current therapeutic strategy for HIV-infected patients is to start antiretroviral therapy with HAART in order to avoid the accumulation of resistance towards drugs in less suppressive regimens. In a second study, we showed that the start of HAART in antiretroviral-naive HIV-patients in daily clinical practice could prevent viral breakthrough for up to 44 months in 60% of patients (n = 25). Six of 10 patients with virologic failure developed resistance to the drugs included in their treatment regimens. In comparison to patients with a sustained virologic response, patients with virologic failure were in a later disease stage when starting therapy and showed lower PI drug-levels, what can be an indication of poor adherence. Despite a poor virologic response for some of them, a rise in CD4 cell count was observed for all patients during the study period. A large number of HIV-infected patients started treatment in the pre-HAART period. The use of NRTIs is mono- or bitherapy was not able to prevent the development of resistant virus. In a third study we studied the prevalence and characteristics of 2 patterns of multinucleoside resistance (MNR) in European patients (n = 755). In patients without NRTI-exposure or with exposure to only one NRTI, no MNR was observed. MNR was present in low prevalence (each pattern < 2%) in patients pretreated with multiple NRTIs. Despite this low prevalence, MNR should be closely monitored, since it results in broad cross-resistance to NRTIs in vitro and a poor therapy response in vivo. We also assessed the predictive value of baseline resistance on the virologic response to later added drugs. The genotype of patients starting or changing a therapy consisting solely of NRTIs was analyzed at baseline and 6 months later. In patients without genotypic mutations towards the added drug the virologic response was significantly better compared to patients with baseline resistance. At 6 months however, both patient groups showed a rise in viral load due to the accumulation of NRTI-related mutations under the presence of poorly suppressive regimens, although the difference between the two groups remained significant. In this study, and also in studies reported by others, the presence of baseline resistance has a high predictive value for therapy failure, while the absence of resistance is not predictive for therapy response. Suboptimal adherence may be one of the reasons of the poor predictive value of the absence of baseline resistance for a good therapy response. In a last observational study, we investigated the relation between adherence, the presence and development of genotypic resistance and the virologic response in patients during HAART therapy. Adherence to 1 protease inhibitor was monitored using Electronic Event Monitoring. Patients with perfect therapy adherence and in particular without drug holidays, can control viral replication provided that the activity of the drugs included in the combination is not entirely compromised by the presence of baseline resistance mutations. In our patient population, reduced adherence resulted in therapy failure, mostly associated with a subsequent accumulation of resistance mutations. In conclusion, the outcome of the HIV disease has been revolutionarily changed with the advent of HAART. Both resistance and treatment adherence are crucial factors in determining the therapy response. Retrospective studies, such as ours, and a limited number of prospective trials already proved the short-term benefit of therapy switch based on the results of resistance tests in addition to standard of care. To ultimately define the role of tools as resistance testing and adherence monitoring with eventual adherence interventions, more prospective trials are needed as well in treatment-naïve as in experienced patients.