Report on International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies - June 4-8, 2013 Toronto, Canada
International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies
June 4-8, 2013
Mark A. Wainberg
McGill University AIDS Centre, Montreal, Canada
1. Anti-HCV Drugs
This year the International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies was held in Toronto, Canada and was successful in regard to imparting new information in regard to treatment and resistance issues associated with each of these viruses. The conference opened on the morning of Wednesday, June 9th with an excellent overview of Hepatitis C virus by Dr. Stuart Ray of John Hopkins University who discussed the wide array of drugs that are now available for treatment of this mutation. Dr. Ray made the point that the new drugs that are already or will soon be available will make an enormous difference in regard to our ability to manage this disease. At the same time, however, he expressed doubts that HCV treatment would be sufficient to eliminate the HCV epidemic or HCV transmission and said that issues of drug resistance would continue to be important. He drew strong parallels between HCV and HIV in regard to the mutational strategies of these viruses and the ability of each to evade antiviral drug pressure.
His presentation was followed by a series of abstract presentations on the topic of HCV, led by C. Hedskog of Gilead Sciences (Abstract 1) who evaluated patients who possessed the S282T mutation after relapse after having initiated therapy with sofosbuvir (SOF). Sequencing of the N55B gene was carried out by deep sequencing using an array of each of baseline samples and samples collected at two days after start of monotherapy and at each of weeks 4, 8, 12, 24, and 48 thereafter. The results showed that very low levels of the S282T mutation were present after initiation of therapy. The data suggest that low level variants containing S282T at baseline may have been amplified following monotherapy with SOF. However, the fact that the viruses containing the substitution were no longer detectable at later time points during therapy i.e. 24 and 48 weeks, suggests that the viruses in question may have reverted to wild-type (wt). The presence of such wt variants could have been due to reversion as opposed to outgrowth of the baseline wt population. These findings suggest, among other things, the potential for SOF to be used in treatment after development of resistance against this drug. The field will await future studies on the use of SOF in the treatment of Hepatitis C virus infection as well as to the approval of this very exciting nucleoside analogue anti-HCV drug.
IDRW: Evolution of the HCV Viral Population from the One Patient with S282T Detected at Relapse after Sofosbuvir Monotherapy (06/09/13)
In Abstract 2, M. Ehteshami et al continued the discussion on anti-HCV drugs, and spoke about DAPN compounds that are novel nucleoside inhibitors of HCV. In particular, prodrugs of DAPN, termed DAPN-PD, can be metabolized into distinct phosphate variants inside the cell and these metabolites possess anti-HCV activity. The results show that DAPN-triphosphate (DAPN-TP), which is a major metabolite, was able to directly inhibit HCV polymerase activity. The presence of the S282T mutation conferred approximately 10-fold resistance against the DAPN-TP, by interfering with chain termination. The fact that the DAPN may be metabolized into two distinct active forms that mimic A and G nucleotide analogues in their triphosphate forms may result in possible synergy between these substances and may prevent the emergence of drug resistance. The field looks forward to extension of these interesting observations and to the clinical development of these compounds.
Abstract 4 by V Cento et al was presented by F Ceccherini-Silberstein and was on the topic of NS3- resistance mutationas in HCV patients who were treated with boceprevir or telaprevir for 24 weeks. Sequencing identified resistance in five out of eighty-two individuals within four weeks of initiation of therapy with these protease inhibitors (PIs). In some cases, these patients were previous non-responders who failed with mutations including V36M and R155K. The results further showed that early detection of drug resistance either at baseline or at 48 hours after initiation of therapy was associated with ultimate treatment failure to these drugs in individuals who had previously been non-responders. These findings point to the relevance of resistance testing as a means of predicting treatment failure.
In Abstract 5, K. Chan et al presented data on a novel screening assay for detection of new anti-HCV drugs using a GT3a replicon system in HUH-7 cells. This method has been developed by scientists Gilead Sciences. The results show that this method will be useful for the screening of new compounds that may be used in the treatment of HCV disease. This will hopefully give rise to new anti-HCV drugs in the future.
IDRW: In Vitro Efficacy and Resistance Profiling of Protease Inhibitors Against a Novel HCV Genotype 3a Replicon (06/09/13)
Abstract 6 by O. Lenz et al was on the use of Simeprevir (formally known as TMC435) to treat HCV disease. This compound is a novel once-daily anti NS3/4A protease inhibitor that is currently being studied in phase III clinical trials for infection of individuals with HCV genotypes 1 and 4. The data show that mutations that may be associated with HCV drug resistance to this drug include those at positions S122G, S122N, and S122T, that are baseline polymorphisms that do not seem to affect Simeprevir activity in culture. R155K was observed at time of failure in 14 of 44 patients and a D168V mutation was observed at treatment failure in 23 of 44 individuals. Further characterization of this drug is awaited in regard to the mechanism whereby resistance is conferred by these mutations and their potential effect on therapeutic success involving the use of Simeprevir.
In Abstract 37, G. Kukolj and colleagues presented on the emergence of resistant variants in individuals infected by HCV who were treated with the NS3 protease inhibitor Faldaprevir. This compound is currently being evaluated in Phase III studies and it has been previously demonstrated that mutations at positions R155K and D168V may confer resistance in genotype 1a and 1b virologic failures. These findings have also been substantiated in the current study which also demonstrate that median times to appearance of resistant viruses containing the aforesaid mutations may be 11 and 8 months, respectively, in regard to the R155K and D168V substitutions. A polymorphism at positions Q80K was not significantly associated with reduced virologic responses and Q80K does not seem to be substantially associated with lessened responsiveness to Faldaprevir. It should also be noted that the D168V mutation may confer a fitness impact in regard to viral replication, perhaps more so than R155K, although the clinical significance of this observation is not yet understood. The field looks forward to the further clinical development of Faldaprevir and its benefit for patients infected by HCV.
Abstract 39 by A De Luca and colleagues was on the topic of genetic difference among HCV genotypes. Sequence analysis in this study has confirmed that a variety of HCV-1a subtypes seem to exist in the circulation. One of these, termed Clade 1, may be associated with a higher prevalence of the Q80K polymorphism. This is of concern since this may potentially lead to a greater likelihood of resistance to Simeprevir and/or other drugs in the clinic.
2. Resistance to New anti-HIV agents
Abstract 21 by MR Underwood and colleagues dealt with studies on the use of dolutegravir (DTG) to treat antiretroviral (ART)-experienced individuals who were otherwise na´ve in regard to use of an integrase strand transfer inhibitor in the SAILING study. The participants in this trial possessed resistance to some of the compounds that were used as part of the regimen together with DTG, and, it was previously demonstrated at CROI 2013 that DTG performed in superior fashion to RAL in this setting in regard to virological responsiveness. However, a small number of individuals with viral rebound in the DTG arm of the SAILING study developed a mutation at position R263K in integrase that had been previously selected in tissue culture by DTG. The current study extends these findings by showing that virologic failure was more frequent after therapy of this population with RAL (9%) compared with DTG (4%), in spite of the fact that the R263K mutation was identified only in the case of two individuals who received DTG. In contrast, patients who failed on RAL usually developed mutations known to be associated with resistance to the latter drug. It is uncertain to what extent R263K may be responsible for clinically relevant resistance, since the change in IC50 associated with this substitution was less than 2-fold for each of DTG and RAL. The results of this Abstract further show that DTG remains strongly associated with the integrase protein in biochemical assays, even if mutations at positions R263K or V260I or both are present. This suggests that DTG may retain antiviral activity even in the presence of R263K. It is likely that DTG will be approved for clinical use within several months and the field looks forward to further experience with this compound as well as to patient benefit from it.
IDRW: Integrase Genotypic and Phenotypic Predictors of Antiviral Response to Dolutegravir (DTG) in Subjects With Resistance to Integrase Inhibitors (INIs) (06/11/13)
Abstract 22 was on the topic what has long been referred as a backup integrase inhibitor to DTG termed GSK1265744, hereto referred to as GSK744, that is thought to have potential for long term usage in the form of either oral administration or injection for the treatment of HIV disease. The investigative team led by T. Yoshinaga that studied this compound attempted to select for resistance to it in culture and was unsuccessful, suggesting at the very least that this compound possesses a very high genetic barrier toward resistance. They also studied the effect of GSK744 in regard to viruses containing multiple other mutations associated with HIV-1 drug resistance to integrase inhibitors, and found that GSK744 maintained broad activity against all of the mutated viruses and enzymes that were studied. Despite this, however, some viruses containing mutations within the Q148/G140 pathway possessed a degree of resistance against GSK744, suggesting that the resistance profile of this compound is likely to be similar to that of DTG. It is hoped that GSK 744 might be used together with another long lasting compound available for use as an injectable, i.e. Rilpivirine, and a combination of GSK744 with Rilpivirine for use in this context may be compelling.
IDRW: Advanced Mechanistic Studies of GSK1265744, a New HIV Integrase Inhibitor (INI) Dosed by Oral Administration or Long-Acting Parenteral Injection (06/11/13)
CROI/2012: PrEP GSK744 Integrase Administered Monthly Perhaps Quarterly Prevents HIV-Infection in Monkeys - (03/07/13)
In Abstract 29, CL Vavro et al presented on patients enrolled in the VIKING-3 study who received therapy with DTG at a dose of 50 mg twice-daily in combination with other drugs after first having failed therapy with Raltagravir (RAL). The findings indicated that mutations associated with resistance to Raltagravir at positions 148 and 140 may be associated with treatment failure in the context of attempts to use DTG in a second line regimen. This Abstract is of relevance in regard to the potential for DTG to be used in sequencing strategies following first failure RAL or with a different integrase strand transfer inhibitor that has now also been approved for therapy, i.e. elvitegravir (EVG). This is due to a commonality of mutations and cross-resistance associated with each of RAL and EVG. The investigators were unable to determine precise integrase resistance phenotype cut-offs in regard to DTG and in attempts to predict antiviral responsiveness. It should, however, be pointed out that most patients in the VIKING -3 trial did respond well to DTG when this compound was used in therapy, i.e. 82% of subjects showed excellent responsiveness with a drop in viral load of at least 1 log. The accumulation of resistance mutations in some individuals between days 8 and week 24 were predictive of failure in some cases. It should be recognized that there may be patients who will depend on the use of DTG as part of a salvage strategy should few treatment options be available after prior failure with RAL or EVG. In the event that DTG turns out, as shown thus far, to possess a higher genetic barrier for resistance than either RAL or EVG, will this result in a situation in which sequencing argument is used that would favor the use of DTG as part of a salvage strategy as opposed to first line therapy? This is a question that will surely be asked by the field in the future, although the answers to this question may not yet be available or obvious.
These data also make clear that DTG can be used in the vast majority of cases to successfully treat patients who have failed a Ral-containing regimen. Of course, it must be noted that the number of patients who do fail while on Ral are very limited and that the latter drug has been shown to be superior to use of Efavirenz over five years of follow-up in regard to sustainability of suppression of viral RNA to below 50 copies RNA/ml of plasma.
In all likelihood, similar findings would be expected for individuals who may ultimately fail an EVG containing regimen, however rare this may be. The overlapping resistance mutational profile of EVG and Ral will preclude the possibility that either of these drugs might be used to salvage the other, meaning that DTG will likely be the only integrase inhibitor to have utility as part of a second-line regimen after failure with either Ral or EVG in first-line.
The above data sets are also suggestive of the following. First, DTG is likely to be more effective than either Ral or EVG for treatment of patients who have previously failed drug regimens that did not contain an integrase inhibitor. This is likely to be due to the higher genetic barrier to resistance of DTG versus either Ral or EVG in a context in which the other drugs in the regimen may be compromised because of problems of resistance and cross-resistance. However, it should be noted that no clinical data are yet available on this topic in regard to EVG and this is mostly because EVG has been available in clinical practice for a relatively short time compared to Ral that has now been used in HIV therapy for more than 5 years. Nonetheless, it is known that the resistance profiles of EVG and Ral overlap extensively in regard to the mutations within the integrase gene that are associated with resistance and that resistance against both Ral and EVG can be selected in tissue culture far more easily than is the case for DTG.
IDRW: Evolution of Integrase in Virus at Protocol-Defined Virologic Failure From the VIKING-3 Study (06/11/13)
Glasgow/2012: Antiviral Activity of Dolutegrevir in Subjects With Failure on an Integrase Inhibitor-Based Regimen: Week 24 Phase 3 Results From VIKING-3 (1) Poster - (11/16/12)
In Abstract 28, PK Quashie et al selected in tissue culture for resistance against DTG and identified a G118R mutation within the integrase gene as potentially associated with very low level drug resistance. In some cases, this mutation was selected in combination with a different substitution at position E138K. These substitutions were primarily associated with low-level resistance against DTG in subtype C viruses, raising the possibility that different mutational resistance profiles may emerge in viruses of different subtypes, as has previously been noted for other types of anti-HIV compounds, including both nucleoside and non-nucleoside reverse transcriptase inhibitors. Some degree of cross resistance in regard to G118R was also observed in regard to RAL (raltegravir). The G118R mutation also led to reduced replication fitness, which was further exacerbated in the presence of E138K. This suggests that viruses that possess resistance against DTG may be limited in regard to their ability to grow and to be detected in patient samples. The study of patients by more ultrasensitive methods such as deep sequencing may be required in order for the presence of resistance mutations against DTG to be detected in the clinic.
Abstract 23 by N. Margot et al was presented by C. Callebaut of Gilead Sciences and was on the topic of Tenofovir alafenamide (TAF) that is a novel prodrug of Tenofovir (TDF). The former compound has previously been shown to be active in Phase II clinical trials involving HIV-infected patients. However, it may be active at far lower doses than that which is currently used for TDF. Most important, the use of TAF may result in less toxicity than the use of TDF. The results demonstrate that the resistance profile of TAF and TDF are similar. The K65R mutation and others mutations studied, including an assortment of thymidine associated mutations (TAMS), the Q151M complex, or T69 insertions, with or without M184V were all associated with varying degrees of drug resistance to TAF. Nonetheless, TAF seems to possess superior antiviral potency than does TDF in tissue culture and may lead to higher intracellular levels of the active form of this compound i.e. tenofovir diphosphate. One question that remains to be asked is whether TAF may be able to maintain activity against individuals who possess the K65R mutation that is associated with clinically meaningful resistance against TDF. One of the reasons why this is important is that relatively high numbers of subtype C infected patients in developing countries, who have been treated with antiviral nucleosides, have developed the K65R mutation at treatment failure. Although this has been more common with the antiviral drug stavudine than with TDF, it has also been reported in regard to use of the latter compound. Ideally, TAF will maintain activity against K65R-containing variants because of its superior pharmacokinetic profile and its ability to generate high levels of active anti-viral diphosphate inside the cell. Hopefully, Gilead Sciences will design a clinical trial to investigate this topic more fully. In all likelihood, TAF will be developed as a substitute for TDF in the context of combination nucleos(t)ide and NNRTI antiviral therapy in the treatment of HIV disease for both na´ve and treatment-experienced subjects.
IDRW: Antiviral Activity of Tenofovir Alafenamide (TAF) against Major NRTI-Resistant Viruses: Improvement over TDF/TFV is Driven by Higher TFV-DP Loading in Target cells (06/09/13)
Abstract 24, presented by C. Soulie and colleagues was on the topic of a novel attachment inhibitor termed BMS-626529 that possesses activity against both R5- and X4-tropic isolates of HIV-1. Treatment with this compound has previously been shown to reduce viral load, but mutations at positions M476L and S375M in envelope may be associated with reduced susceptibility to this agent. Patients demonstrating reduced susceptibility against BMS 6266529 were shown to have the M426L mutation in a number of cases, sometimes in association with S375T, S375N, or S375M. This notwithstanding, resistance against this compound was observed in relatively small numbers of individuals and the field looks forward to its further development for possible use in anti-HIV chemotherapy.
Frequency of amino acid changes associated with resistance to attachment inhibitor BMS-626529 in R5- and X4-tropic HIV-1 subtype B (06/12/13)
Abstract 30 was on the topic of drug resistance in the context of the STaR study. This work presented by DP Porter and colleagues was on the use of co-formulated Rilpivirine/Emtricitabine/tenofovir (RPV/FTC/TDF) as a single tablet, when studied in comparison with the single tablet regimen known as Atripla (EFV/FTC/TDF). The results of studies on this topic have shown that RPV/FTC/TDF was in general non-inferior to EFV/FTC/TDF in regard to suppression of viral load to below 50 copies per ml. The resistance data associated with this study showed that very few patients receiving RPV/FTC/TDF developed resistance against RPV or the other drugs in the regimen. However, resistance to more than one component of this regimen was far less frequent in individuals who began therapy with viral load <100,000/ml compared to >100,000/ ml. Accordingly, these findings are consistent with treatment recommendations that RPV/FTC/TDF be used as first-line therapy in individuals who possess fewer than 100 000 copies viral RNA per ml. It is important to point out that previous studies have indicated that successful therapy with RPV/FTC/TDF can be pursued in individuals who began therapy with high viral loads i.e. greater than 100 000 per ml, if treatment was first initiated with a PI-containing regimen i.e. protease inhibitor + TDF/FTC for several months in order to fully suppress viral load followed by a switch to RPV/FTC/TDF.
IDRW: Primary and Secondary Analyses of Emergent Drug Resistance through Week 48 from the STaR Study: Rilpivirine/Emtricitabine/Tenofovir DF vs. Efavirenz/Emtricitabine/Tenofovir DF Single-Tablet Regimens (06/14/13)
3. Interpretations of Low Level Resistance
In Abstract 31, KJ Metzner and colleagues investigated the clinical significance of minority species of HIV containing mutations at positions K103N and 181C that are associated with resistance against members of the NNRTI family of drugs. The question that was asked is whether or not all patients should be screened by ultra-sensitive methodologies for detection of these mutations in regard to future clinical benefit that involve the use of such drugs as efaverenz (EFV) in therapy. Indeed, a number of previous studies including meta-analyses have reported that the presence of such minority NNRTI-associated mutations can be associated with treatment failure. Now, these investigators have evaluated 1437 patients in the Swiss HIV cohort for genotypes prior to initiation of therapy with 2 NRTIs and 1 NNRTI prior to July 2008. Of this number, 519 individuals met the criteria for evaluation that included the availability of plasma samples for study at six months prior to initiation of therapy and a viral load that was greater than 1000 copies RNA per ml at baseline. In addition, these subjects had to have demonstrated an absence of mutations to both NNRTIs and NRTIs on the basis of population-based sequencing. The detection of mutations at K103N and Y181C was carried out by allele-specific PCR in 221 of the 519 subjects that were chosen at random. A total of 202 patients were available for follow-up study. The results of this evaluation showed that none of the patients who harboured a K103N minority variant went on to experience virologic failure (i.e. 5 of 174 subjects), while one individual who had a pre-existing 181C minority species did fail a first line regimen. The authors conclude that it will be a poor use of limited resources to recommend that ultrasensitive analysis be implemented for study of all patients about to enter therapy for the first time, as the possible presence of low-level minority variants, at least as detected by AS-PCR, may not have clinical significance.
This abstract stood in contrast with Abstract 32, presented by LC Swenson et al, who performed a similar analysis through evaluation of multiple samples on the basis of 454 ultrasensitive sequencing. The results showed that the presence of minority populations containing resistance mutations could be associated with ultimate treatment failure in regard to the proportion of patients who successfully suppressed viral loads to below 50 copies viral RNA per ml. There was a further correlation with genotypic sensitivity score (GSS), with the likelihood of ultimate treatment failure being higher with a high GSS. One possible conclusion from these two presentations is that the use of ultradeep sequencing may be more sensitive than AS-PCR methodology in regard to predictions of the clinical significance of low-level minority species containing drug resistance mutations in regard to ultimate treatment success or failure.
This conclusion may also be supported by the findings of Abstract 33, presented by A. Cozzi-Lepri et al, who conducted a retrospective study within six observational European cohorts in regard to HIV-1 infected individuals who did not have pre-existing NNRTI resistance on the basis of population sequencing and who were then evaluated by 454 sequencing as well. The results showed that the presence of minority variants that included mutations at positions M184I, V108I, and V75I may have been associated with higher risk of virologic failure, particularly in cases in which more than one such mutation was present at baseline on the basis of 454 sequencing. Thus the presence of pre-existing minority resistant variants may increase the risk of virologic failure. However, it should be pointed out in context that most patients performed well when receiving anti-HIV therapy in regard to viral load reductions, despite the possible presence of minority variant resistant species prior to treatment initiation. These findings further indicate that 454 sequencing and/or other ultradeep sequencing methodologies may be more sensitive than the use of allele-specific PCR with regard to predictions of ultimate treatment outcome and the significance of minority resistant viral variants.
HIV Persistence and Viral Reservoirs
An excellent overview of the topic of HIV persistence and attempts to immunologically deal with the topic of viral reservoirs and latency was presented by Dr. Nicolas Chomont of the Viral Gene and Therapy Institute of Port-St-Lucie, Florida. In his lecture (Abstract P2), Dr. Chomont spoke of the need to find a cure for HIV given the spread of this virus throughout the world, problems of drug resistance and toxicity, and cost issues associated with therapy. Dr. Chomont discussed mechanisms that could involve the ultimate control of viruses that exist within latent reservoirs. Among the methods suggested were such cytokines as IL-7. However, it was pointed out that some substances, including the latter, may exert pressures that suppress viral replication, while simultaneously promoting the sequestration of latent viruses within reservoirs. It is important to point out that it was Dr. Chomont and colleagues who first observed the importance of the Tcell central memory compartment as a reservoir for HIV infection within the body. Clearly, the field is now galvanized toward researching methods that will enable us to deal with the problem of long-lived viral latency and potential eradication of HIV from within the body of infected individuals.
These and other topics were also discussed in a series of abstract presentations. First, TA Wagner and colleagues (Abstract 15) followed a single pediatric patient over time and observed that identical envelope sequences were located within identical integration sites in cells that were obtained from this individuals. This finding unquestionably points to the fact that proliferation of infected cells occurred within this person. Furthermore, these findings indicate that multiplication of HIV-infected cells may be important in regard to establishment of HIV reservoirs.
In Abstract 16, E. Anderson and colleagues also observed that viruses that possess identical or nearly identical sequences can be detected in individuals being treated with antiretroviral therapy. This is supported by observations of clonal viremia in patients regardless of treatment and within whom a number of drug resistance mutations have been observed. These findings are also consistent with the notion that proliferation of HIV infected cells is an important contributor to viremia. This Abstract and the one previous indicate that proliferation of HIV infected cells may occur to a far greater extent than has previously been thought and that such cells may be of great importance in regard to establishment of viral latency and persistence.
Abstract 18 was presented by MF Kearney and colleagues and was on the topic of a genetic evaluation of monkeys that were infected with a RT-SHIV hybrid virus. The animals were followed over time in regard to viral variability, and samples were evaluated from both plasma and tissues. The results showed that the virus population that exists within in plasma and tissues are well mixed within the animals, suggestive of recombination between the populations and interflow between tissue compartments.
Does this mean that a successful strategy aimed at HIV eradication will need to simultaneously deal with multiple tissues and blood compartments? Probably, the answer to this question is Yes, making the idea of even a fuctional cure for HIV more daunting than if only single reservoir types needed to be considered.
Abstract 19 was presented by AM Geretti and colleagues and was on the subject of whether low-level viral replication can occur despite the successful use of antiretroviral chemotherapy. In this study, 18 patients who began first-line therapy with an NNRTI-based regimen were observed to have a decline in levels of viral DNA within cells over time. However, despite this, viral RNA was able to persist in plasma as determined by use of an ultrasensitive assay capable of detection of as few as ten copies viral RNA per ml. The viral DNA declines in the face of viral RNA persistence suggests, in the view of these authors, that ongoing viral replication may not have occurred in these individuals despite the presence of viral RNA in plasma.
Abstract 20 was presented by JZ Li et al and was on the relationship between inflammation and low-level viremia. It was shown that elite controllers were more likely to have possessed markers of monocyte activation than were individuals negative for HIV infection. Elite controllers were also likely to have detectable levels of interferon gamma, IL-10 but not other monocyte activation markers. The investigators conclude that factors other than viral loads are likely to contribute to the presence of inflammation and elevated markers of inflammation.
Finally, an excellent plenary lecture was presented by Dr. Edward Holmes (Abstract P3) on the topic of viral RNA evolution over time. Dr. Holmes compared numbers of different viruses in regard to ability to mutate and differentiate over time. This intriguing lecture provided everyone in the audience with food for thought in regard to possible control of future viral epidemics. Dr. Holmes mentioned that progress in regard to HIV control was important and that lessons would be learned from the HIV experience in regard to other viral epidemics. In particular, the topic of pre-exposure prophylaxis (PrEP) and Treatment as Prevention (TasP) both exemplify how anti-retroviral drugs (ARVs) might be used to control HIV transmission. Of course, multiple potential obstacles are still present in regard to potential success including issues of drug resistance. Nonetheless, success or failure in regard to attempts to limit HIV transmission in real-world settings through use of ARVs will be instructive for similar approaches for other viral diseases,
It is noteworthy that the organizers of the conference took special effort to include several sessions on the topic of Hepatitis C virus pathogenesis and drug resistance in addition to the usual focus on HIV-1. It is hoped that future conferences will deal with the subject of viral drug resistance in a more general way and will include other viruses besides HIV and HCV, since common mechanisms seem to exist among all viral agents in regard to development of drug resistance.