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Report on the International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies - June 7- 11, Cabo, Mexico
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Written for NATAP by Mark A. Wainberg, McGill University AIDS Centre, Jewish General Hospital, Montreal, Canada
"HIV Prevention and Drug Resistance in Resource-Limited Settings.....5 of 6 animals receiving the TFV gel were completely protected after more than 20 exposures to the virus-resistant virus......TFV gel has the potential to be active against both drug-resistant as well as wild-type viruses, despite the fact that levels of protection against these two variants may be different.....overall presence of transmitted drug resistance remains low, but patterns of mutational development among individuals developing drug resistance in resource-limited settings are similar to results obtained in developed countries......Persistence, Reservoirs and Elimination Strategies.....a naturally-occurring compound termed ST057704......Margolis and colleagues presented data on non-linear decay of resting CD4 cell infection after retroviral therapy during acute infection.......Detection of Low-Frequency Mutants and Their Clinical Significance in HIV, HCV & HBV......Max Lataillade and collegues collected data from an ultra-deep sequencing analysis of samples from HIV-infected individuals who were treated with the combination of raltegravir and atazanovir in the SPARTAN study. This clinical trial was a pilot study designed to evaluate the efficacy of combination therapy with non-boosted atazanovir plus raltegravir, both administered twice daily, in treatment-naïve subjects.....NS3 and NS5 regions of the HCV genome by ultra-sensitive 454 sequencing.....the importance of access to ultra-sensitive sequencing as a powerful method to study HBV drug resistance"
XMRV: Lessons Learned for Microbe Hunters
Dr. John Coffin presented a plenary lecture on the topic of XMRV. This virus had been associated, on the basis of previous studies, as a possible cause of both prostate cancer and chronic fatigue syndrome (CFS). A number of manuscripts have now appeared in the literature that refute the likelihood that XMRV is associated with either of these conditions. XMRV stands for Xenotropic MLV-related virus, and was first described approximately 6 years ago in several cases of prostate cancer. Following this, molecular analysis had documented that XMRV was present in prostate cancer tissues and was also found in blood samples from individuals suffering from CFS. However, evidence is now compelling that XMRV probably arose during the past decade as a recombinant virus as a result of tissue culture manipulation in the laboratories of several retrovirologists. Moreover, the evidence that XMRV is the cause of either CFS or prostate cancer is now very limited, and more specific analyses have failed to detect XMRV in any clinical samples that have more recently been examined. Indeed, Dr. Coffin's group has been key in refuting any linkage of XMRV to human disease, although he has contributed to data sets showing that endogenous viruses that are almost identical to XMRV might be found in certain tissues. These findings are important because of evidence that many CFS sufferers, who were desperate to improve their health conditions, had resorted to the use of antiretroviral drugs as a possible treatment for their CFS condition. In addition, evidence was mounting that men fearful of developing prostate cancer had also turned to antiretroviral drugs as a means of minimizing their likelihood of developing this condition. Clearly, the use of antiretroviral medications would not have rationale in regard to either of these conditions and might potentially have been harmful, given that a number of side effects are associated with the use of virtually all members of the antiretroviral families of drugs.
This presentation and work that has been carried out by a number of different laboratory groups, that refute the putative role of XMRV in human disease, are important. It is important that conclusions of causality not be reached for any human condition based on relatively few observations in regard to potential viral or microbiological etiologies of diseases of unknown origin. Recently, groups of young parents have refused vaccinate their children against measles virus for fear that toddlers might succumb to autism, despite a total absence of evidence linking measles virus vaccine and autistism. As a consequence, thousands of additional needless cases of measles may have occurred in recent years. And, we are all aware of how HIV denialists have probably caused many thousands of individuals to have died through denial of lifesaving antiretroviral medications to HIV- infected persons. The current research also reinforces the necessity to duplicate findings in multiple laboratories prior to concluding that any particular agent may have an etiological association with a human disease condition.
Mechanisms of HIV Drug Resistance
A number of abstracts at the conference were on the topic of mechanisms that are involved in the development of HIV resistance to antiretroviral drugs.
In Abstract 4, the group of Celia Schiffer (S. Mittal et al) presented data in regard to mechanisms whereby non-active site mutations might be responsible for drug resistance against protease inhibitors. In brief, it has long been recognized that mutations within the protease gene itself can affect the ability of protease inhibitors to bind to the protease enzyme target. Now, these investigators have used X-Ray crystallography as a method to understand how alterations in core flexibility within the protease enzyme might affect the ability of the protease enzyme to cleave various substrates. Accordingly, a number of crystal structures were analyzed under varying conditions in the presence of the well-known inhibitor termed darunavir (DRV). A number of striking differences were observed in the hydrophobic core region of the enzyme that was engineered to contain a relevant disulphide bond. The results document that a restriction of hydrophobic core dynamics is one of the mechanisms that may modulate the ability of the HIV protease enzyme to function. Mutations within protease that are located outside of the active site can influence the ability of substrates to be recognized by the enzyme. These observations also provide important information on how these various mutations affect both the rigidity of wild-type and mutated drug-resistant protease enzymes and provide information as to how the development of a more rigid protease structure might also lead to virus variants that are less replication-fit than either wild-type viruses or viruses that are mutated at other positions within the protease enzyme. These findings have the potential to increase our understanding of protease function and, as well, to lead to new drug development based on these novel results in regard to protease enzymatic function.
In Abstract 5, D. Descamps and colleagues have conducted studies relating to genetic determinants within the gag region of HIV-2 in regard to attempting to demonstrate conditions that might be responsible for protease inhibitor resistance on the part of this virus. It is well known that HIV-2 is a more rare viral infection than is HIV-1. Nonetheless, infection by HIV-2 is also subject to multiple clinical complications, and, if left untreated, can lead to profound immune suppression followed by death. Now, this group has studied the impact of mutations within gag and has shown that virologic response among 46 patients was successfully observed among many who received PI-containing regimens. The drug that was principally studied in this context was lopinavir boosted with ritonavir (LPV/r), i.e. Kaletra. When virologic failure occurred after three months of therapy, this was most commonly associated with higher baseline viral loads. In addition, a greater number of resistance mutations in PR were associated with prior treatment with other PIs as opposed to the use of LPV/r in PI-naïve patients. Two mutations in gag that were associated with resistance were T435A, which is located at the cleavage junction of NC/P6, and V447M, located at the junction between P1/P6. Both of these were associated with a mutation within PR at position Y114H. This is the first documentation of an association between mutations within gag and those within PR in HIV-2-infected subjects. These findings are important because they provide testimony to the importance of mutations within the gag region and particularly at gag cleavage sites in regard to the development of resistance against protease inhibitors in HIV-2, complementing information already available for HIV-1. Although most of these findings were obtained among 14 of 17 PI-naïve patients and 17 of 29 PI-experienced patients, generalization to the field of HIV-2 infection is probably warranted. However, it is unknown whether the development of cleavage site mutations or mutations within PR arose first in regard to the ultimate documentation of resistance. In addition, it is unknown whether or not HIV-2 variants that contain cleavage site mutations are sensitive to Bevirimat, a HIV-1 maturation inhibitor against which certain cleavage site mutations were demonstrated as having importance in regard to occurrence of drug resistance.
In Abstract 6, V. Svicher and colleagues discussed the role of the VI, V2, and C4 domains within the viral envelope of HIV-1 in the modulation of interactions between viral GP120 and CCR5 and CXCR4. This study is important because it sheds light on the manner whereby these interactions may affect HIV antigenic potential. Accordingly, this is also important work in regard to potential HIV vaccine development.
The study investigated GP120 sequences from 286 infected individuals. The authors showed that key patterns of GP120 residues were significantly associated with phenotypically defined usage of either CCR5 or CXCR4 co-receptors. The GP120 residues in question lie outside of the V3 region and are primarily associated with V1, V2, and the C4 domains.
The introduction of specific mutations at position 398 within viral envelope was shown to decrease CCR5-binding affinity on the part of the viral envelope. This work therefore further advances our knowledge in regard to key genetic elements within these extra-V3 regions in regard to modulation of HIV-1 dependency on either CCR5 or CXCR4 as a portal of entry. An important conclusion is that V3 alone is not sufficient for a full and comprehensive analysis of understanding HIV tropism based on genotyping. Until now, considerable effort has been made by a number of groups in regard to sole reliance on genotyping as a determination of tropism. The current research suggests that further study of this issue is necessary. In view of the fact that there is growing consensus that maraviroc may be an under-utilized drug, this subject is important and meritorious of further attention by attention by physicians, researchers, and patient groups.
Abstract 7 by F. Hong et al was on the topic of detection of nevirapine-resistant HIV-1 variants that emerged in mothers following use of single-dose NVP over periods of 7 vs. 21 days. The background of this study is that previous work that had employed single-dose nevirapine for prevention of mother-to-child transmission had shown that subsequent treatment with either TDF/FTC or ZDV/3TC or LPV/r had been effective at suppression of resistance to NVP as determined by standard population-based genotyping. Indeed, these findings had also shown that resistance to NVP had emerged less commonly after 21 versus only 7 days of subsequent therapy. The current study investigated the use of an allele-specific PCR reaction to determine whether or not consistent findings would be obtained in comparison to those mentioned above. A total of 116 subjects were evaluated, mostly on the basis of an allele-specific PCR assay for the K103N mutation that is associated with resistance against both NVP and EFV. In some cases, results were also obtained in regard to the Y181C mutation that is also associated with resistance to these two members of the NNRTI family of drugs. The results documented that the various secondary treatment regimens studied were indeed effective at suppressing the emergence of drug resistance to NVP as monitored by allele-specific PCR as well as by routine genotyping. This notwithstanding, the occurrence of resistance in regard to NVP was more common when only 7 days of treatment (as opposed to a 21-day regimen) had been employed. These findings highlight the need to provide follow-up therapy of women followed for PMTCT by use of drug regimens over 21 days as opposed to only one week.
Abstract 8 by J Z Li et al was on the topic of adherence to NNRTI-based therapy and the emergence of low-level resistance. These investigators studied a total of 768 individuals who were followed as part of a previously established data set in regard to development of NNRTI resistance. The results show that patients who were least adherent to their ARV regimens had a higher risk of virologic failure than those who were more adherent. In addition, the likelihood of detection of minority NNRTI resistance mutations, as observed on the basis of ultra-sensitive and routine sequencing, was increased on the basis of non-adherence to drug regimens. In addition, these investigators observed that the presence of minority mutations conferring drug resistance to NNRTIs was also associated with an increased risk of virologic failure, regardless of levels of adherence to antiretroviral drugs. Indeed, the presence of such minority NNRTI drug-resistant variants was apparent in individuals who were adherent to anti-retroviral drugs and who subsequently went on to treatment failure. This study underlines that adherence, while an important consideration in the development of HIV drug resistance, may not be a sufficient explanation in multiple cases in terms of determining whether or not certain individuals might be prone to develop minority viral species that are resistant to NNRTIs and who may subsequently fail treatment regimens.
Detection of Low-Frequency Mutants and Their Clinical Significance
This is an extremely important topic in regard to many different types of viral infection. The reality is that the presence of drug resistance mutations at levels that cannot easily be detected by standard techniques may nonetheless have strong clinical significance. Considerable evidence now indicates that the presence of such drug resistance mutations may lead to treatment failure in regard to a variety of viral infections.
In Abstract 22, the group of C. Rodriguez et al presented data on the topic of Hepatitis B virus infection. This group isolated samples from 119 baseline and serial serum samples taken over approximately 2 years of therapy on adefovir from 7 patients who had developed resistance against this drug. Sequencing was carried out by usual methods as well as by 454 ultrasensitive genomic sequencing. The results revealed the presence at baseline of minority variants representing approximately 0.1-0.5% of the quasi-species that contained substitutions that are known to confer resistance to available anti-HBV drugs. These included mutations at positions M204V/I, N236T, A181V/T, and T184F/A/I/L. In the case of individuals failing adefovir monotherapy, the adefovir-resistant viruses became dominant over time. This study clearly documents the importance of access to ultra-sensitive sequencing as a powerful method to study HBV drug resistance. In addition, this study documents that monotherapy with any single anti-HBV agent is likely to lead to the development of drug resistance and that any form of monotherapy should be discouraged. It is necessary to convince the world of HBV treaters that monotherapy for this condition can no longer be tolerated and that combination anti-viral therapy is a basic necessity in regard to HBV therapeutics.
Abstract 23 presented similar results in regard to resistance on the part of HCV to antiviral drugs. In this study, samples from 18 patients from the phase II PROVE-2 trial were analyzed by ultra-deep sequencing. The existence of a number of mutations known to confer resistance to anti-HCV drugs, such as telaprevir, was documented. The most frequently occurring substitutions were those at positions R155K/T/Q, A156S/T/V, V168A/V/T/H, and I170A/T. The results also documented that a variety of telaprevir-resistant variants were present at baseline and that additional mutations could be selected by telaprevir over time in patients who had received monotherapy for treatment of their HCV infection. The evidence suggests, as in the case of HBV and HIV, that monotherapy will be likely to select out drug resistant variants of HCV and that combination antiviral therapy will be a basic necessity in regard to future therapeutics. Given the wide array of new anti-HCV drugs currently being developed, it seems likely that consensus will emerge in short order as to the need to carry out combination antiviral chemotherapy for treatment of HCV.
In Abstract 24, evaluations were carried out in regard to resistance against HCV NS3 protease inhibitors by E. S. Svarovskaia and colleagues. This work involved sequencing of the HCV NS3 protease region using 454 ultrasensitive methodology. The patients in question had received monotherapy with either of two Gilead HCV NS3 protease inhibitors, GS-9256 or GS-9451, over 1-3 days. The results document that there was an absence of drug resistance mutations at baseline. However, 19 of 27 patients developed drug resistance mutations within NS3 after 2 days of therapy, and this was seen in 21 of 21 patients who received monotherapy after 4 days. Similar findings were observed with either of the study drugs, accompanied by increased viral loads between days 2 and 4, concomitant with the emergence of drug resistance. It was also demonstrated that the replication fitness of all of these drug-resistant variants was significantly lower than that of wild-type virus. These results are consistent with the notion that drug resistance mutations must pre-exist prior to HCV therapy and that the use of monotherapy will quickly select for pre-existing drug-resistant variants. Hence, there is a compelling need for combination therapy in regard to HCV therapeutics.
Abstract 25 by S. Margeridon-Thermet and colleagues was on a similar theme in regard to sequencing of the NS3 and NS5 regions of the HCV genome by ultra-sensitive 454 sequencing. These investigators studied samples from 39 treatment-naïve HCV-infected subjects of varying genotypes. They showed that there was an absence of resistance mutations at baseline but that numbers of subjects developed mutations associated with drug resistance at various times after initiation of therapy. The concordance between results obtained by ultra-deep pyrosequencing and molecular clonal analysis was very high, i.e. 87%, in regard to detection of minority drug resistance variants. These results also point to the diversity of the HCV genome which seems to be genetically more diverse than that of either HIV or HBV. In addition, the HCV polymerase may be more error prone than that of either HIV or HBV. The conclusion that minority variants can easily be detected in the aftermath of therapy is clearly important and again provides testimony to the compelling need for combination antiviral chemotherapy. It should also be recognized, however, that current paradigms for therapy of HCV involve combinations of interferon and ribavirin. At the present time, the influence of IFN and RBV on development of resistance against rationally developed anti-HCV drugs remains to be determined.
In Abstract 26, Max Lataillade and collegues collected data from an ultra-deep sequencing analysis of samples from HIV-infected individuals who were treated with the combination of raltegravir and atazanovir in the SPARTAN study. This clinical trial was a pilot study designed to evaluate the efficacy of combination therapy with non-boosted atazanovir plus raltegravir, both administered twice daily, in treatment-naïve subjects. Over 24 weeks of therapy, the combination of these two drugs was as effective as comparable drug regimens used as part of standard of care. In the current study, the investigators wished to determine the clinical significance of resistance mutations that were documented by ultra-deep sequencing methodologies. The results documented that 12.7% of 63 subjects treated with ATV plus RAL had baseline variants that included RAL resistance mutations at positions Q148R, G140S, and Y143C/H. After 24 weeks of therapy, 6 subjects experiencing virologic failure were evaluated, of whom 4 had resistance to RAL on the basis of mutations at positions N155H and Q148R. Two individuals presented with the Q148R substitution and one had a Q148R minority variant at low frequency. Of the subjects who developed resistance, no-one showed phenotypic resistance to atazanovir while on study, in spite of the fact that 5.7% of individuals had an ATV baseline resistance mutation. There was also a relationship between high baseline viral load and likelihood of treatment failure with the regimen that was used. However, most RAL mutations were not amplified by treatment with RAL, calling into question the basis of treatment failure in these individuals. These results notwithstanding, it seems obvious that combination therapy involving RAL and ATV is unlikely to be repeated, given the high rate of individuals who developed drug resistance mutations in this study.
Abstract 27, by A. Poon et al, presented by P. R. Harrigan, was on the topic of ultra-deep sequencing analysis of the V3 loop within HIV envelope to predict use of CXCR4 variants within different patient compartments. These investigators analyzed samples from PBMCs and serum, and evaluated samples taken at 3-month intervals up to 1 year prior to the first phenotypic detection of X4-using variants in MT2 cells. The results showed that the estimated time to use of X4 receptors was 15-68 months from estimated time of HIV infection. These estimates were not as high in PBMCs as in plasma, pointing to possible age differences between viruses identified in plasma vs. cellular compartments. Indeed, mean time to use of CXCR4 was 20.6 months in regard to plasma and 13.8 months for PBMCs. These results document that CXCR4-using variants are probably present for approximately 1 year or more before the detection of relevant samples in M2 cells. The results also suggest a more rapid turnover of virus populations in PBMCs than in plasma. This raises the question as to whether plasma may be seeded from a different source than PBMCs. This is a question of longstanding debate in the field and further work will be necessary to further clarify this issue.
Persistence, Reservoirs and Elimination Strategies
This important topic was first broached in Abstract 28, presented by N. Sluis-Cremer who described a naturally-occurring compound termed ST057704. This compound was tested either alone or in combination with other inhibitors of transcription in regard to potential blockage of HIV replication. Specifically, assays were used to study histone deacetylase (HDAC) enzymes or kinases. The results show that the ability of HIV-1 to be reactivated from latent cells was significantly diminished in the presence of ST057704. In addition, the combination of ST057704 together with other compounds that block transcription yielded even more impressive results. Biochemical assays have confirmed that ST057704 can play this role and further suggest that HDAC inhibitors can be important in regard to activation of cell latency. Unfortunately, however, ST057704 did not display any inhibitory activity on its own against any class 1 HDAC enzymes that were tested. These results suggest that compounds belonging to a ST057704 series may perform in similar fashion to previously described SAHA molecules but may have even more compelling activity than the latter. The field of histone deacetylase inhibitors merits further investigation and finding ways of activating HIV-1 expression from latency remains a key challenge toward eventual eradication of the virus.
In Abstract 29, D. M. Margolis and colleagues presented data on non-linear decay of resting CD4 cell infection after retroviral therapy during acute infection. These investigators studied 22 acutely infected patients who provided both plasma and cellular samples. The investigators observed that peak levels of viremia and duration of viremia prior to antiretroviral therapy could be correlated with the frequency of initial resting cell infection kinetics. The results also showed that resting cell infections diminished significantly in patients who received antiretroviral therapy, although variations could be observed among individuals in this regard. The investigators concluded that higher initial levels of resting cell infections may gave rise to less stable populations of cells that may decay following several years of antiretroviral therapy. However, patients who contained their resting cell infections at baseline may have more stable populations that may resist antiretroviral therapy. The levels of such cells in chronic infection may, however, be larger and more stable than in acute infection. Further studies will be required to determine whether more effective means can be found of dealing with the resting cell infection (RCI) pool and to determine why this pool might persist despite the use of antiretroviral therapy. Conceivably, homeostatic cell proliferation could also play a role in maintenance of these cellular pools that have so far defied eradication. These findings are important in regard to development of strategies aimed at HIV eradication.
Abstract 30 by M. Kearny and colleagues was on a similar topic in regard to persistence of HIV populations in plasma after long-term use of antiretroviral therapy. These investigators have used single-genome sequencing and have documented that HIV populations that persist may be more closely related to ancestral sequences than are populations obtained at later points but prior to initiation of therapy. These findings were obtained on the basis of phylogenetic analysis and suggest that clonal sequences that are detected in chronically infected individuals may be the result, in part at least, of relative loss of some divergent sequences due to death of infected cells. However, certain clonal expansions cannot be excluded, especially since some of these studies were conducted at times that exceeded 9 years of therapy. The fact that older variants have apparently persisted over this long period provides important testimony to the importance of the initial viral population that successfully seeds itself during acute infection. These results may provide added impetus to the notion that acutely infected individuals should be treated as early as possible in order to prevent diversification of the HIV-1 infecting population to as great an extent as is possible.
HIV Prevention and Drug Resistance in Resource-Limited Settings
Abstract 31 was on the topic of vaginal tenofovir (TFV) gels in regard to HIV transmission in macaques. Specifically, C. Dobard et al presented data showing that the use of TFV gel might be effective against both wild-type isolates of virus as well as against isolates containing the K65R mutation that is known to be responsible for resistance against TFV. Here, the investigators employed a recombinant HIV/SIV virus termed a SHIV. This is a virus that is mostly SIV but that contains that a HIV-1 reverse transcriptase gene.
The system that was utilized in this study was pig-tailed macaques and PBMCs derived from these animals. The investigators injected the animals with the viral construct and also employed TFV gel for purposes of prophylaxis. The results showed that the virus containing the K65R mutation was 5-fold more resistant to TFV than was wild-type virus in tissue culture. This notwithstanding, 5 of 6 animals receiving the TFV gel were completely protected after more than 20 exposures to the virus-resistant virus. In contrast, only 4 of 6 animals that received a placebo gel were infected after a median of 5 challenges. This shows in definitive terms that the gel was able to maintain a protective influence against the drug-resistant virus. These data were complemented by pharmacology studies in macaques that showed that lymphocytes in vaginal tissues had very high levels of the active form of TFV, i.e. TFV-diphosphate, at 4 hours following dosing.
These data are important because they document that the use of TFV gel has the potential to be active against both drug-resistant as well as wild-type viruses, despite the fact that levels of protection against these two variants may be different. Hopefully, these findings can be followed up by a clinical trial that will address this same issue, given that the development of safe and effective microbicides may be key toward prevention of infection among female populations who may not always be empowered to employ other means of protection against HIV while in situations of risk.
Several abstracts dealt with the topic of the presence and prevalence of drug-resistant variants of HIV-1 in developing country settings. In Abstract 32, R. K. Gupta et al presented data that included a weighted analysis of proportions of individuals who possess at least one drug resistance mutation. These findings showed that the overall prevalence of transmitted drug resistance was 3.8%. More importantly, however, they showed an increase over time in the proportion of viral samples containing at least 1 drug resistance mutation in low- and middle-income countries from 2.5% in 2007 to 3.3% after 2007. Higher levels of drug-resistant viruses that were newly transmitted were observed in Latin America vs. Eastern Europe, and even lower levels were observed in Asia and Southern Africa. This may reflect access to drugs in these various geographic regions over time. When the analysis was limited to recent infections only, no major differences were observed in regard to transmitted drug resistance in these various geographic areas. Alarmingly, the investigators observed that 48% of patients in Sub-Saharan Africa who showed any type of baseline resistance were likely to have mutations associated with the NNRTI family of drugs although no differences were observed between recent vs chronic infections. This probably reflects the fact that NNRTI mutations do not have significant impact on viral replicative capacity or fitness. The results further document that increases in transmitted drug resistance over time may be most common in portions of Eastern Africa. These findings clearly demand that studies on transmitted drug resistance continue to be carried out in resource-limited settings as well as in developed countries in the future.
Abstract 33 by M R Jordan et al was on a similar theme in regard to follow-up of transmitted drug resistance. These investigators conducted an analysis of 53 studies on transmitted drug resistance performed in 22 countries between 2004-2009. They observed that there is, in general, a low prevalence of transmitted drug resistance in regard to all drug classes. However, higher levels of transmitted drug resistance have been observed for the NNRTI family of drugs and related mutations than for other drug classes. The results further document that the most common resistance-associated mutations were K103N (30%), Y181C/I (31%), M184I/V (52%) and G190A (13%) among treated populations. These results are, of course, consistent with data that have been observed in other settings. Thus, the overall presence of transmitted drug resistance remains low, but patterns of mutational development among individuals developing drug resistance in resource-limited settings are similar to results obtained in developed countries in which antiretroviral drugs have been available over much longer periods of time. These results suggest that routine virological failure is associated with the development of drug resistance and that virological monitoring might be able to identify virologic failures at earlier stages. This is important in terms of maximizing opportunities for patient benefit from second-line regimens.
Abstract 34, presented by A. D. Revell, was on the topic of neural networks as predictive tools to determine the presence and significance of HIV drug resistance. These investigators have developed models to assess whether computer modelling might be able to assist with predictions of virological responses based on patient genotype, viral load, CD4 counts and treatment history. The models presented were highly efficient at predicting responses to antiretroviral therapy based on the considerations outlined above. Clearly, further refinement of this method will be necessary in years to come. The field is encouraged by the fact that these models will be available for different geographic regions, an important consideration since viral subtypes may play an important role in regard to development of specific mutations associated with resistance against different drugs. Hopefully, as well, this method may be highly cost-effective in regard to developing countries that cannot easily afford to conduct routine genotyping and that certainly do not have access to high-resolution genotyping techniques such as allele-specific PCR and pyrosequencing.
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