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  XVII International AIDS Conference
Mexico City
3-8 August 2008
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IAC Mexico City 2008 Summary Report
  Mark Wainberg, McGilll University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada
The 17th International Conference on AIDS, held in Mexico City between 3-8 August 2008, featured a number of important papers in the fields of HIV therapeutics and drug resistance. Some of these papers and the implications that they bring forward for consideration are as follows:
HIV Therapeutics
In abstract TUAB0102, Markowitz et al presented data on the sustained antiretroviral efficiency of raltegravir when used as part of a combination ART regimen in treatment naive subjects at 96 weeks. Readers will recall that Markowitz has previously reported on individuals treated with the combination of raltegravir plus tenofovir plus 3TC over time periods of 24 and 48 weeks. The current results on randomization of 198 individuals to receive raltegravir plus 3TC/TFV or raltegravir/3TC/EFV now indicate excellent sustainability of responsiveness over a full 96 week time period. It should be noted that patients were all switched from earlier varying doses of raltegravir to receive the standard approved dose of 400mg bid after 48 weeks. The results document sustainability of an approximate 4.7 log reduction in levels of viral RNA, with over 84% of the cohort remaining non-detectable for viral RNA (<50 copies RNA/ml) after 96 weeks. Importantly, both arms of the study appear to have performed equally well over this period, in spite of the fact that earlier results had reported faster drops in viral load immediately after initiation of antiviral therapy. After 96 weeks of treatment, both arms of the study documented rises of approximately 200 CD4 cells. Although one individual on the raltegravir arm relapsed, no mutations in this individual were observed after 48 weeks of therapy. In contrast, a patient who relapsed on EFV possessed both the 103N and 184V mutations, associated with resistance against efavirenz and 3TC, respectively. A greater number of drug-related adverse events were reported in the efavirenz than raltegravir arms of the study, i.e. 74% versus 51%, respectively.
Abstract TUAB0104 by Sierra Madero and colleagues was on the topic of treatment of patients with advanced disease, i.e. CD4 counts < 200, receiving initial therapy with either an EFV or boosted lopinavir-based regimen. This was a prospective randomized trial that compared EFV versus LPV/r in patients who also received AZT/3TC. Of 189 patients randomized to each of these two arms, the proportion of individuals who had viral loads < 50 copies of viral RNA per ml after 48 weeks was 70% after treatment with EFV versus only 54% after treatment with LPV/r. In an intent to treat analysis, that examined viral load levels below 400 copies after 48 weeks, the percentages of non-delectability were 73% after treatment with EFV versus 65% after treatment with LPV/r. CD4 cell increases were approximately the same in both arms of the study after 48 weeks, i.e. 156 with EFV versus 166 versus LPV/r. Discontinuations were reported in 27% versus 34% of individuals receiving EFV and LPV/r, respectively, and this is an obvious confounder in the study, that may also not have been adequately powered to permit direct conclusions in regard to non-inferiority. Indeed, it stands to reason that levels of adherence to therapy may also have been higher in the EFV arm, since that drug only needed to be dosed once daily and pill burden was higher with the lopinavir/r soft-gel capsules that were employed. Analysis of treatment failures of patients with residual viral load in regard to resistance mutations remains to be carried out.
Abstract THAB0303 was a late breaker study presented by P. Sax et al. This investigation examined the use of ABC/3TC versus TDF/FTC in the context of ACTG study 5202. This was an evaluation in a phase 3b randomized 4-arm study of treatment naive patients who received double blind ABC/3TC versus TDF/FTC plus open-label EFV or ATZ/r. Patients were stratified on the basis of viral RNA levels at base-line that were either higher or lower than 100,000 copies per ml. A total of 797 individuals of 1858 who were screened possessed RNA copy numbers at base-line > 100 000. Over follow-up of 60 weeks, the results now demonstrate that time to virological failure was shorter in individuals receiving ABC/3TC than in those receiving TDF/FTC, i.e. 57 versus 26 subjects, respectively, showing viral load rebounds to > 50 copies/ml after initial viral load suppression. A secondary analysis revealed that the proportion of patients achieving non-detectability i.e. < 50 copies per ml after 48 weeks of therapy, was 75% versus 80% for patients on ABC/3TC versus the TDF/FTC arm of the study, respectively.. In addition, patients receiving ABC/3TC seem to have developed higher incidence rates of adverse events, that mostly related to general body ache and lipid increases during the study period, as well as shorter times to appearance of lab abnormalities that were at least one grade higher than base-line. These results do not take into account whether patients might have been treated with either EFV or ATZ/r as additional drugs used as part of the triple drug regimens that were employed. Further analysis will be necessary to confirm and extend these observations. The interpretation of results may also be complicated by the fact that patients were permitted to switch off of ABC in favor of TDF, such that the intent to treat analysis included such individuals who were not considered to be failures.
Abstract THAB0304 was another late breaker by K. Pappa et al, that was motivated by study ACTG5202 that had reported earlier times to virological failure in patients receiving ABC/3TC compared with TDF/FTC. In this instance, the investigators examined virological burden in individuals who participated in the above study, based on stratification at base-line in regard to viral load. Now, Pappa et al have conducted an analysis based on 48 week efficacy data among 2940 previously ART-na夫e patients. The results demonstrate that almost all individuals, i.e. 87% - 95%, did not experience virological failure, on the basis of similar analytical methods as those previously used to study responsiveness in the ACTG 5202 study. The current analysis of 6 different clinical trials in this GSK-sponsored study documented that patients receiving the combination of ABC/3TC, together with other drugs, performed well irrespective of base-line viral load.
Abstract THAB0404 was also a late breaker study presented by T. Campbell et al on ACTG study A5175, also referred to PEARLS. This was an international collaborative analysis of the combination of enteric-coated ddI (ddI-EC)/FTC/ATZ versus ZDV/3TC/EFV for use in na夫e patients in a variety of treatment settings. The rationale for use of a ddI-EC/FTC/ATV regimen is obvious, since this once ミdaily combination might be relatively inexpensive, not require refrigeration of antiretroviral drugs, and have relevance in a number of developing country settings. A total 1045 individuals were enrolled in this study. Unfortunately, the results demonstrated that ZDV/3TC/EFVwas superior to the ddI-EC/FTC/ATZ arm both in regard to viral load as well as CD4 rebounds after 96 weeks of therapy. As a consequence, patients who had been enrolled into the ddI/FTC/ATZ arm of the study are now being switched to take other drugs in replacement of ddI-EC.
A pivotal study was THAB0405, also a late-breaker, in which C. Klein et al presented data on a new formulation of ritonavir i.e. a 100 mg film-coated tablet. This is a new product that does not require refrigeration and will therefore have multiple advantages over the current 100 mg soft gelatin capsule. A comparative study in healthy adult subjects has now documented in a single dose, open label, 2 period cross over study in 93 subjects that both formulations appear to be bio-equivalent, on the basis of area under the curve data. This is an important study that now sets the stage for use on a wide-spread basis of this new film-coated formulation of ritonavir. No differences in regard to safety of either the soft gelatin capsule or the new film-coated tablet were reported.
Abstract TAHB0406 was also a late breaker presentation in which Y. Yazdanpanah et al reported on the use of raltegravir together with etravirine and darunavir/r in treatment-experienced patients who possessed multiply drug-resistant viruses. This study, referred to as the ANRS139 TRIO protocol, examined patients who had failed previous drug regimens and who now possessed plasma viral loads in excess of 1000 copies/ml. These individuals also possessed at least 3 mutations associated with previous use of protease inhibitors and 3 or more mutations associated with use of nucleoside compounds. However an exclusion criteria at entry was that patients also had to have had fewer than 3 PI mutations, associated with darunavir, and 3 or fewer NNRTI mutations that might compromise the use of etravirine. The results of this analysis, based on 103 patients, with an average treatment history of 13 years, showed that 55% of them achieved undetectable viral load after 4 weeks and that 91 patients, i.e. 8%, achieved undetectable viral loads after 12 weeks of treatment. These results were sustainable to week 24 on the part of 93 of 103 patients. Only one individual had a viral load > 400 copies per ml after this time. Increases in CD4 counts were a median of 99 cells and only one patient had to discontinue therapy due to rash. Accordingly, the combination of raltegravir, etravirine and darunavir/r appears to represent an excellent option for individuals with previous treatment failures and multiply drug-resistant HIV.
New Antiretroviral Agents
In abstract TUAB0103, M. Santoscoy et al presented data on 96 week follow-up data in antiretroviral na夫e patients of rilpivirine (TMC-278), a new NNRTI. Studies on this compound after 48 weeks of therapy had previously been reported at CROI in 2006. The current results extend these observations and now document that TMC-278 possesses durability in regard to efficacy of antiviral response. In addition, TMC-278 appeared to be well tolerated in subjects who received this drug over 96 weeks, regardless whether blinded dosing was with TMC-278 at 25mg, 75mg, or 150mg administered QD. The comparator agent was EFV dosed at 600mg QD and all individuals received either ZDV/3TC or TDF/FTC. The results of this analysis that involved 368 individuals also showed that all doses of TMC-278 were efficacious, resulting in viral load reductions to < 50 copies RNA/ml in over 70% of patients, findings similar to those that were obtained in the EFV arm. CD4 cell increases after 96 weeks were also comparable, in the range of a 146-159 cell increase after 96 weeks with the various TMC-278 dosing regimens versus 160 cells for EFV. Similar results were also reported in regard to adverse events (AEs) in the various TMC-278 arms versus EFV. Not surprisingly, it appears as though there may also have been more AEs in patients who received ZDV/3TC than TDF/FTC. These results indicate that TMC-278 is likely to continue to be developed and will play an important role in the clinic in years to come.
In abstract TUAB0106, novel data were presented on the safety profile of Apricitabine (ATC), a novel NRTI being developed for use in salvage therapy for patients who have developed resistance against previous nucleoside-containing regimens. In particular, this compound appears to be highly efficacious in individuals who have developed the M184V and/or L74V mutations, and who have few remaining options in regard to NRTI therapy. The results of a 24 week analysis in which ATC was dosed at either 600mg or 800mg bid in combination with other antiretroviral drugs revealed an absence of serious adverse events in the study population. Furthermore, there were no apparent discontinuations due to the use of ATC. This paper demonstrates that ATC seems to be well tolerated and safe over 24 weeks of therapy in combination with other drugs, creating further rationale for the development of this compound and its use in treatment-experienced patients who possess resistance to multiple other members of the NRTI family of compounds.
Abstract THAB0402 was a late breaker by C. Zala et al on the topic of a novel NNRTI, also being developed for use in HIV patients who have previously failed a NNRTI-containing regimen and who possess NNRTI resistance mutations. A novel compound, termed IDX899, has now been tested in 30 treatment na夫e patients with HIV RNA viral loads > 5000 copies per ml. Three different doses of drug were used, i.e. 800mg, 400mg, or 200ml QD over 7 days. The results of this study in na夫e patients demonstrated a mean viral load reduction of approximately 1.8 logs in the context of monotherapy. CD4 rebounds were approximately 65 cells during the same time period and all 3 doses of IDX899 achieved trough levels that were higher than the EC90 value by as much as 5-20 fold. These findings create strong rationale for the further development of IDX899 for use in patients who have a documented history of prior NNRTI treatment, since this compound is highly active in tissue culture against viruses containing NNRTI-relevant mutations such as K103N and Y181C in reverse transcriptase (RT). In addition, of course, these findings also provide justification for ultimate consideration of IDX899 as a drug to be considered for first-line therapy, since it can be dosed once-daily, is well tolerated, and possessed an excellent pharmacokinetic profile.
Abstract THAB0403 was a late breaker by G. Moyle et al on a related topic, i.e. the development of RDEA806, another novel NNRTI being developed by Ardea Biosciences. Earlier phase 1 studies have documented that this compound was safe and well-tolerated. Now, a phase 2a randomized double-blind placebo controlled trial in 48 na夫e patients has tested various doses of RDEA806 over a one-week period. The results document viral load reductions of the order of a median of 1.8-2.0 logs after QD dosing of an enteric-coated tablet. The compound was also well tolerated. Further results can now be anticipated in regard to the continuing development of this compound that might also have applicability for use in either salvage or drug-na夫e patient settings.
Acute Infections
Late-breaker abstract THAB0401 by G. Kamanga was a study investigating the prevalence of acute HIV infection in Malawi. This study is important, because relatively little information is currently available in regard to incidence of acute HIV infection in developing countries. This study screened 6674 individuals and detected 80 acute HIV infections in this population on the basis of PCR analysis. These individuals were negative for HIV antibody in parallel screens and possessed a median HIV RNA viral load at screening of approximately 181, 000 copies/ml. Hence, these studies confirm that unrecognized antibody negative acute HIV infections are an important source of new transmissions and may be present in high prevalence in Malawi in particular and in sub-Saharan Africa in general. Clearly, large numbers of infectious individuals, in view of these high viral loads, are being missed by standard antibody screening techniques and renewed efforts are required to diagnose HIV infection earlier as an important step forward in public health.
Another Late-Breaker abstract on the topic of HIV transmission was presented by S. Attia et al in abstract THAC0505. This study examined cohorts of sero-discordant couples in a prospective way and presented a meta-analysis of HIV transmission rates in these populations. A total of 15 cohorts were examined, based on a literature analysis. The investigators concluded that it remains difficult to estimate the risk factors associated with HIV transmission, despite availability of previous data that had attempted to assess risk among HIV positive individuals. The authors expressed concern at the potential negative impact of statements that have suggested that individuals who have been stably treated with antiretroviral drugs for management of HIV disease, and who do not possess detectable virus in their blood streams, may not be considered to be at risk for transmission of HIV.
Circumcision Follow-up
In Late-Breaker abstract THAC0501, RC. Bailey and colleagues reported on a follow-up of the potential protective effects of male circumcision in individuals who were studied as part of a circumcision trial in Kisumu, Kenya. Various studies in South Africa, Kenya, and Uganda have documented a 53-60% protective affect of circumcision over a 24 month period. The results of follow-up over 42 months now document a cumulative sero-positivity of 2.6% among men who received immediate circumcision versus 7.4% among individuals who had agreed to delay this procedure for one year. This translates to a 64% cumulative protective effect of circumcision over the course of follow-up. Indeed, it is conceivable that the effect of circumcision may have been strengthened during the 24-42 month time-frame that followed circumcision in this study population.
Abstract THAC0502 by B. Auvert was another Late-Breaker study on the effect of male circumcision on potential acquisition of agents other than HIV-1. In particular, this group had previously documented that male circumcision protects against acquisition of each of HIV-1 and HSV-2. Now, the current study has documented on the basis of urethral swabs and urine samples that a protective effect was also realized in regard to acquisition of human papilloma virus (HPV) (P < .001). However, an intent to treat analysis was unable to demonstrate significant effects in regard to infection by other agents such as trichomonas vaginalis (TV) and neisseria gonorrhoea. These results help to explain the lower incidence rates of both HPV and TV infections among women whose partners were circumcised. These studies, as do those of abstract THAC0501, also reinforce the rationale for expansion of availability of affordable circumcision to developing countries.
Finally, Late-Breaker abstract THAC0503 by U. M. Parikh et al represents a very important paper on the use of combination FTC/TDF as a topical microbicide gel. In this study, a group of scientists at the Centers for Disease Control in Atlanta, working together with collaborators, applied a gel formulation of TDF/FTC or a placebo gel intravaginaly to 14 macaques. The animals were then subjected to twice weekly vaginal challenge of a hybrid virus termed a SHIV, that includes the reverse transcriptase gene of HIV-1 in a background of SIV (Simian immunodeficiency virus). The results showed that 7 of 8 control animals that received placebo gel became infected after a median of 3.5 challenges. In contrast, 6 macaques that received the FTC/TDF gel were protected against challenge with this SIV after as many as 20 challenges. These results establish proof of principal of the potential use of the combination of FTC/TDF as a microbicide to protect against HIV-1 infection of women at risk and constitute important rationale for the commencement of microbicide human clinical trials based on this concept.
Drug Toxicity
An important area of research is whether or not certain anti-HIV compounds may be associated with heightened risks of toxicities over protracted periods of time. In Late-Breaker abstract THAB0305, J. Lundgren and colleagues presented the results of an analysis from the SMART study, based on exposure of patients to a variety of nucleoside compounds. This research focused particularly on the use of abacavir as an antiviral nucleoside and follows from earlier work from the D:A:D study that had suggested that the use of two different NRTIs, i.e. abacavir and didanosine, may have been associated with an increased risk of development of myocardial infarction (MI). The current study, based on the SMART data sets, further investigated this issue in a non-randomized analysis of three groups of patients. These included individuals receiving abacavir and not didanosine, people receiving didanosine and not abacavir, and people receiving nucleoside compounds other than abacavir or didanosine. The results demonstrated that use of abacavir seems to have been associated with higher rates of cardiovascular disease (CVD) in comparison with use of other NRTIs. The use of comparator nucleosides revealed fewer CVD events; this work also included use of tenofovir as part of a reference population. Individuals showing increased cardiovascular risk also possessed higher levels of C-reactive protein and IL-6 than individuals considered to be at lower risk of cardiovascular illness. This same study showed that ddI did not appear to be associated with higher risk of CVD nor increased levels of IL-6 or C-reactive protein.
A major issue is how to reconcile the data reported in this abstract with earlier results. For one thing, a discrepancy appears to be present in regard to the current study that failed to document any increased cardiovascular risk associated with use of ddI, whereas the D:A:D study did indicate that elevated risk following ddI use may have been an important factor. In particular, it is difficult to juxtapose the current data sets based on the SMART study with those derived from the HEAT trial which was a 96-week randomized double blind comparison of co-formulated ABC/3TC versus TDF/FTC, both in combination with lopinavir/r.
The HEAT trial involved a fairly large data set, i.e. 688 treatment na夫e patients, and seemingly established non-inferiority of co-formulated ABC/3TC versus TDF/FTC in regard to each of clinical antiviral responsiveness as well as issues pertaining to toxicity. These analyses included estimates of diverse events that included diarrhea, nausea, triglyceride levels and glomerular filtration rates. The results of the HEAT study also documented that no patient receiving abacavir or other drugs seemed to be at increased risk of stroke. In contrast, the D:A:D study was an observational analysis of 11 previously analyzed cohorts of patients followed at clinics in Europe, the United States , and Australia. This study sought to examine whether combination antiretroviral therapy might be independently associated with a risk of MI. Patients had received multiple drugs over long periods of time, and the study found that recent use of abacavir may have been associated with increased MI risk, that appeared to disappear after stopping the drug. In addition, the study found that the risk of MI may have been more pronounced in patients with higher levels of underlying coronary heart disease.
Now, most recently, the analysis of the SMART study presented here seems to again suggest that abacavir may be associated with a higher risk of MI. Readers will remember that the SMART study followed a total of 5472 patients randomized to receive either continuous treatment with antiviral drugs or to interrupt therapy. Individuals in the latter group were asked to reinitiate therapy if CD4 cell counts fell to < 250 cells and would then remain on therapy until CD4 rebound occurred to > 350 cells, etc. Although the SMART study was not powered or designed to investigate rates of MI in patients assigned to different nucleoside options, the results showed that abacavir use was more than 3 times as likely to occur in patients with cardiovascular risk factors at study entry.
How is it possible to reconcile these seemingly conflicting results? Clearly, further analysis will be necessary, but it should be pointed out that the HEAT study may not have been adequately powered or continued over a long enough period to answer questions pertaining to long-term toxicity. In addition, it will be necessary to study possible associations of MI risk factors with use of other nucleoside/nucleotide drugs including tenofovir. Indeed, such studies are currently underway and should be reported at future meetings. In the meantime, however, one possible explanation might be that abacavir (ABC) use might indeed be relatively safe when the drug is given as part of a first-line therapeutic regimen but that MI risk factors might increase if ABC is administered later on during the course of disease i.e. in the context of salvage settings and/or treatment interruption protocols in which abacavir might sometimes be used in individuals whose HIV disease relapsed after they were taken off therapy. In other words, some of the potential toxicities attribute to abacavir might be more prone to occur in individuals with more advanced HIV disease, possibly as a consequence of unrecognized consequences of HIV pathogenesis. However, it should be noted that the ACTG 5202 study, discussed above, also reported higher levels of drug related toxicities in previously drug-na夫e patients beginning therapy with ABC/3TC than with TDF/FTC. Clearly, additional study of these and related issues is warranted and the field will be unable to render any final judgement on these and related issues until further studies and analysis have been completed.
Drug Resistance
Resistance following treatment

In abstract TUAA0301, B. Dau et al reported on the development of drug-resistance in the context of a treatment interruption study known as the Optima trial. The question that was asked was whether mutations in the connection domain of the HIV reverse transcriptase (RT) gene might be associated with drug resistance. For this reason, they focused on codons 316-437 within RT and concluded that connection domain mutations frequently occur in this population and probably do have impact on virological outcome. The study certainly adds to the rationale for further evaluation of the role of the connection domain within RT in the context of drug-resistance and also raises concerns as to whether or not connection domain mutations may be able to increase levels of drug-resistance that are the result of thymidine associated mutations (TAMs). In addition, we require further information on whether connection domain mutations may be more likely to occur in individuals who undergo treatment interruptions compared with those who remain on antiretroviral therapy continuously, but who might otherwise be prone to the development of drug resistance.
Abstract TUAA0302 by R Danovich et al was on the important topic of whether resistance against raltegravir might develop differentially in individuals possessing different viral subtypes. This was a sub-analysis of the Benchmrk trials, i.e. large phase 3 randomized clinical trials performed with Raltegravir and other optimized ARVs in treatment experienced patients, many of whom possessed infections caused by non-subtype B viruses. The investigators concluded that raltegravir possessed similar antiviral potency against infections caused by all of the different HIV subtypes that were represented, e.g. C, F, and recombinant forms such as A/E, A/G . Nor were differences in mutational profiles demonstrated in regard to failures on raltegravir, i.e. the same mutations associated with drug resistance in viruses of subtype B origin were also observed in virologic failures in infections caused by other subtypes. In each instance, primary mutational pathways involved either N155H or Y143R mutations, followed by other secondary mutations that have been shown to both augment overall levels of HIV resistance against raltegravir while simultaneously increasing viral replicative capacity
Drug Resistance against HIV-2
This topic is one of growing importance in view of the continuing spread of HIV-2, especially within Western Africa. Abstract WEPE0002 by G. Gottlieb et al studied the presence of HIV-2 drug-resistance in Senegal and showed that HIV-2 infected individuals commonly develop multiple class drug-resistance that includes mutational profiles that include high levels of M184V/I. The Q151M mutation that can cause broad class resistance to all nucleosides was found in 9% of subjects, some of whom also possessed K65R. However, thymidine analog mutations (TAMs) were very rare with the exception of K70R, that was present in one subject, establishing a difference re expectations for HIV-1 infections.
Abstract WEP003 by M. Ntemgwa et al dealt with the presence of polymorphisms and drug selected mutations in HIV-2 and documented that tissue culture selections with a variety of nucleoside compounds favoured the development of the M184I mutation, almost regardless of which compound was used in the selections. In contrast, the K65R mutation developed only rarely, even with NRTIs that select for this mutation in HIV-1, and the occurrence of TAMs was also very rare. These data are consistent with those cited above and establish rationale to pay further attention to the problem of drug-resistance in HIV-2 infections.
Surveillance of transmitted HIV drug resistance
The surveillance of transmitted drug resistance and the existence of country programs to monitor this problem, as well as the choice of methods used toward this end, are of obvious importance. S. Kato et al in Abstract TUAA0201 analyzed the presence of transmitted drug-resistance in a cohort of Japanese patients and were able to show that a novel molecular procedure, based on liquid chromatography-mass spectrometry, was efficient and cost-effective for detection of sexually transmitted minority viral species. This important work underscores the ability of the field to develop assays that are more efficient than those represented by pyrosequencing, which is expensive both in terms of purchase of baseline equipment as well as materials needed to run samples . It will be important to follow the development of this technology in years to come.
In Abstract TUAA0202, L. Banks et al studied transmission of HIV drug-resistance in patients possessing subtype C viruses in South Africa and documented the advantages of studying proviral DNA from blood lymphocytes as well as viral RNA sequences for this purpose. The work showed that availability of whole blood, from which analysis of both viral DNA and RNA may be possible, may be advantageous in comparison to exclusive reliance on plasma RNA for this purpose. In abstract TUAA0203, M. Ofner et al demonstrated that approximately 9% of new infections in Canada possessed at least one mutation associated with HIV drug-resistance on the basis of 3,374 cases that were analyzed. They showed that resistance levels may have been higher in recent (11.5%) compared with established (8.2%) infections, perhaps because mutations associated with drug resistance may sometimes be deselected after transmission but at times prior to commencement of antiretroviral therapy. This also highlights the importance of trying to perform genotypic resistance testing as early as possible after HIV infection has been diagnosed.
Work on the presence and transmission of drug-resistance mutations in different geographic settings was also presented. For example, P. Parenti et al (abstract MOPDA206) from Argentina showed that the prevalence of primary resistance associated mutations in new infections ranged between 12-15%. R. Barrero-Barreto et al ( Abstract MOPDA205) demonstrated that Mexican pediatric patients showed no evidence of transmitted drug-resistance. In abstract MOPDA204, R. Hamers et al documented that screening programs for detection of resistance are now in place in Zambia and that approximately 5% of Zambian adults beginning first-line therapy possessed at least one resistance-associated mutation. Although these are obviously sobering data, the fact that screening is now in place is encouraging. Hopefully, this will lead to the establishment of further infrastructure throughout Africa in regard to the monitoring of drug resistance and drug resistance mutations.
Abstract MOPDA201 by S. Reuter et al from Germany was on the subject of relatively high levels of transmitted drug-resistance in that country. The overall prevalence of viral samples containing resistance-associated mutations in new infections was 9.7%. The investigators also followed patients over time in regard to performance on antiretroviral therapy, to determine whether baseline resistance might have affected responsiveness to HAART. Over 96 weeks of follow-up, the results revealed an absence of significant differences between the groups based on whether or not resistance-associated mutations had been transmitted and were present in pre-therapy samples. But, there are caveats. For one thing, the presence of pre-existing mutations had been ascertained by genotyping and had been taken into account in regard to subsequent choice of antiretroviral drug regimen. In any event, these findings reinforce the importance of performing genotypic testing prior to deciding which antiretroviral drugs should be used in first-line therapy.
Subtypes and Resistance
R. Hamers et al (MOPDA204) documented that approximately 97% of all Zambian viruses analyzed were subtype C, raising the important subject of whether or not differences in drug-resistance mutational profiles might be anticipated in different geographic settings, based on viral subtype and other considerations .
In Abstract TUAB0105, M. Hosseinipour et al investigated the development of drug-resistance among patients in Malawi who had mostly received a first-line antiretroviral therapy of d4T/3TC/NVP, arguably a regimen that would no longer be used in any developed country. Subjects failing therapy were usually switched from this regimen to ZDV/3TC/TDF/lopinavir/r, and, in the event of toxicity, patients may also have been switched before evidence of failure from d4T to ZDV and from NVP to EFV. This prospective analysis evaluated the development of resistance in 101 individuals who were confirmed as treatment failures, all of whom possessed viral loads >1,000 copies of viral RNA per ml, and showed, as expected, that the most common mutation observed was M184V. Not surprisingly, this was followed by a number of NNRTI mutations associated with diminished responsiveness against NVP/EFV, but it was also documented that 16% of the patients who were genotyped possessed either the K65R or K70E mutations that were, in this case, associated with failure in regard to d4T. These findings confirm earlier data from Botswana that had suggested that the K65R mutation was far more likely to occur among patients failing a d4T-containing regimen in the context of subtype C viruses then would be expected with subtype B viruses, and these new findings may be of considerable significance, in view of the fact that both K65R and K70E are able to confer broad cross-resistance against a wide array of nucleoside compounds. Not only may this have the potential to compromise future therapy with the NRTI family of drugs, but there may also be implications in regard to HIV prevention strategies.
For example, the observation that K65R may be selected with greater frequency in subtype C than subtype B viruses raises concern about the potential transmission of the K65R substitution and the impact that this might have on public health, in regard to use of ARVs in therapy. Furthermore, concern also must be expressed in regard to studies that employ antiretroviral nucleosides as prophylaxis to try to prevent HIV spread. Is it possible, for example, that some individuals who enroll in clinical trials in studies on pre-exposure prophylaxis (PREP) and who receive TDF/FTC may actually be in the window period of infection i.e. possessing high viral loads while still being sero- negative? Is it possible that such subjects will select for the K65R mutation as a result, since they will be infected and possess high viral loads, while effectively being treated with sub-optimal therapy ? PREP studies are vitally important and should definitely move forward, but it is now also apparent that surveillance mechanisms must be in place to carefully monitor for the presence of the K65R mutation, especially in geographic areas in which subtype C viruses are predominant. In this context, it is not a trivial concern that over 50% of all new HIV infections worldwide are now attributable to subtype C viruses.
Abstract TUPDA201 by Giang et al documented higher than usual levels of the Q151M mutation in a sampling of Vietnamese patients receiving antiretroviral therapy, although the reason for this above average presence of Q151M, associated with broad cross-resistance against almost all NRTIs, is unknown. Abstract TUPDA202 by Dumans et al documented the presence of drug-resistance mutations in the protease genes of patients with subtype B and subtype F infections in Brazil and suggested that subtype F infections might be less prone to development of protease-associated mutations than subtype B strains. Presentations on surveillance and development of drug resistance in patients receiving antiretroviral therapy were also reported from Mexico (abstract TUPBA203), Argentina (abstract TUPDA204) and India (abstract TUPDA205) as well as other countries.