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AUGUST 2007
Main Article:
Perspective:
Conference Coverage: The 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention Rafael Campo, MD Professor of Clinical Medicine Division of Infectious Diseases University of Miami School of Medicine Disclosures:Speaker's Bureau: Abbott Laboratories, Gilead Sciences, and Merck & Co.; Advisory Board: Abbott Laboratories and Monogram Biosciences; Clinical Grants: Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck & Co., and Virco. Introduction The 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention took place in Sydney, Australia, from 22-25 July 2007. As the premier summer HIV conference (alternating with its sister meeting, the International AIDS Conference), the IAS meeting is a great venue for the presentation of ground breaking HIV-related research. New data on currently available antiretroviral agents, the management of medication-associated toxicities, and the ever-evolving paradigm on when to start therapy were presented. Most exciting were presentations of data dealing with new antiretroviral agents in new drug classes. Lastly, data on antiretroviral resistance, tropism testing, and management of HIV-related morbidities and co-infections rounded out the meeting. Although there were no sessions or presentations dedicated to the care of the incarcerated HIV-infected individual, the results of a number of major studies have a bearing on how HIV is treated in prisons and jails and elsewhere. Current antiretroviral agents and treatment strategies The newest of the protease inhibitors (PIs), darunavir (DRV), has been seen by many as a potentially valuable addition to the HIV armamentarium especially for the treatment of antiretroviral experienced patients. The TITAN study compared DRV 600 mg/ritonavir (r) 100 mg BID (n=298) to lopinavir (LPV) 400 mg/r 100 mg BID (n=297) over 48 weeks in antiretroviral therapy (ART)-experienced, LPV-naïve patients.1 Both groups of patients received an optimized background regimen with two or more nuceloside and/or non-nucleoside reverse transcriptase inhibitors (NRTIs/NNRTIs). Results are shown in Table 1. Because the lower limit of the 95% CI did not go below -12% for either of the two primary outcome measures (proportion with a viral load <400 copies/ml and <50 copies/ml at 48 weeks) for the DRV/r arm, DRV/r was shown to be non-inferior to LPV/r. In fact, because the lower limit of the confidence limits for both of these endpoints did not go below 0, DRV/r was shown to be superior to LPV/r by both criteria. A related sub-study analyzed the response according to the number of LPV-associated resistance mutations at baseline.2 Since none of these patients were LPV-experienced, these mutations had obviously been selected through the use of other PIs prior to enrollment in this study. Although a formal statistical analysis was not presented, the results suggested that the responses to LPV/r and DRV/r are similar in patients with virus with <6 LPV mutations (Figure 1). Not surprisingly, it was for virus with >6 LPV mutations for which DRV/r seemed to be more effective than LPV/r. These findings were similar to the ones stratified by phenotypic fold changes: The outcomes were similar as long as the LPV fold change stayed <10; for patients with LPV fold change between 10 and 40, DRV/r was more effective than LPV/r. Thus, it seems that these data can be interpreted in a relatively straightforward fashion: for patients with lower level PI resistance ( <6 LPV mutations and/or <10 LPV fold change on phenotypic resistance testing) the efficacy of the two PIs is comparable; with higher level PI resistance (>6 LPV mutations or >10 LPV FC) DRV/r appears more effective than LPV/r. A very interesting study by Mallal and colleagues dealt with the prevention of hypersensitivity reactions (HSR) in patients starting Abacavir (ABC) through pharmacogenomic testing ABC-naïve subjects (n=1956) about to start an ABC-containing ART regimen were randomized 1:1 to either be monitored for HSR through standard-of-care observation or to undergo prospective testing for HLA-B*5701.3 Previously, it had been reported that persons with this HLA type were more susceptible to HSR induced by ABC. In the prospective testing arm, those patients negative for B*5701 went on to receive the ABC; those who tested positive did not continue participation in the study. The endpoints of the study were clinically suspected (but not immunologically confirmed) ABC HSR and clinically suspected, immunologically confirmed ABC HSR. The immunological confirmation was carried out through skin patch testing, a research tool not available clinically. The incidence of clinically suspected ABC HSR was lower in the prospective screening arm than the standard-of-care arm and there were no cases of immunologically confirmed HSR in the prospective screening arm (Figure 2). Thus, the negative predictive value of B*5701 testing was 100%. The authors concluded that prospective B*5701 testing resulted in a "dramatic, clinically relevant and statistically significant reduction in ABC HSR". Testing for HLA-B*5701 is becoming available in clinical labs at a cost of $100 or less. Many discussions at the conference centered on the question of when to start HIV therapy. Data from four large cohort studies were presented. The specific aspects of the studies were different, but the overall message was the same: deferral of therapy is associated with poor outcomes. This conclusion was evident in CASCADE (the current CD4+ count, the nadir CD4+ count, and the time with CD4+ <350 were associated with AIDS and non-AIDS-related deaths), SMART (there was a greater risk of opportunistic infections [OIs], death/OIs, and serious non-AIDS events when ART was deferred for treatment-naïve patients), ATHENA (there was a slower CD4+ decline or better increase in CD4+ numbers if therapy was started with 350-500 vs. 200-350 CD4+ cells), and HOPS (there were fewer instances of NRTI-associated toxicities with ART initiation at higher CD4+ counts).4-7 It seems clear that the pendulum is once more on the swing towards earlier initiation of therapy. In retrospect, the reason why clinicians had moved towards later initiation was because of the lower efficacy, lower genetic barrier, higher pill burden, and greater toxicity of the ART regimens available a few years ago. With the improvements in all these aspects of ART with modern regimens, it is appropriate that we re-examine the optimal time of starting ART. New antiretroviral agents The first phase III 48-week data regarding the use of maraviroc (MVC), Pfizer's CCR5 receptor blocker, in ART-naïve patients were presented at the conference (the MERIT study).8 Patients without resistance to efavirenz (EFV), zidovudine (ZDV), or lamivudine (3TC) were randomized to one of 3 blinded treatment arms: MVC 300 mg QD vs. MVC 300 mg BID vs. EFV 600 mg QD, all with a backbone of co-formulated ZDV 300 mg/3TC 150 mg (CBV) BID. Baseline characteristics were similar for all patients. The MVC QD arm was stopped by the study data and safety monitoring board (DSMB) in January 2006 due to inferior efficacy compared to the two other arms. For non-inferiority to be established for MVC, the lower limit of the 1-sided 97.5% CI could not cross -10%; by this criterion, non-inferiority was proven for <400 c/ml but not for the <50 c/ml endpoint. This means that MVC was found not to be 'not inferior' to EFV (i.e. it was worse) with regard to achievement of a viral load less than 50 copies/mL. Despite the virologic data, the mean change in CD4+ counts was statistically superior for the MVC arm. The rates of discontinuation for MVC and EFV were similar (26.9% and 25.2%, respectively); however, the causes for discontinuation were different: lack of efficacy was higher with MVC (11.9%) than with EFV (4.2%) but adverse events were higher with EFV (13.6%) than with MVC (4.2%). How to put all this together? Taking into consideration that the lower limit of the CI was a bit more stringent than what is typically used (-12%), the efficacy was roughly comparable. While EFV seemed to be more effective from a virological suppression perspective, there is a toxicity price to pay for this higher efficacy, and at the end of 48-weeks this resulted in a wash. There is one aspect of the study that was not presented but may prove to be very important in the long run: the selection of drug resistance. If the greater number of MVC virological failures were accompanied by selection of antiretroviral resistance to MVC or other agents in the regimen but the EFV toxicity failures were not associated with drug resistance, then EFV may be associated with a lesser cost for failure and may end up being a superior drug for naïve patients. This resistance data will undoubtedly be presented at a future conference. Another CCR5 blocker, vicriviroc (VCV), was also studied in the 48-week AIDS Clinical Trials Group (ACTG) 5211 trial.9 ART-experienced patients with CCR5-tropic virus and taking ritonavir-containing regimens were randomized to have VCV at 5, 10, or 15 mg vs. placebo added to the failing regimen for 14 days after which an optimized background regimen (OBR) was started. Crossover from the placebo arm to the VCV arms was allowed for patients with virologic failure after week 16. The lowest dose of VCV was discontinued by the study DSMB because of lower efficacy. As reported previously, the study was eventually unblinded because of eight malignancies (two in the placebo and six in the VCV arms). The data presented suggest that the 10 mg and 15 mg arms of VCV were able to suppress viral replication (Table 2). It is hard to make any statements beyond that observation because of the relatively small number of patients in the study and the paucity of other available information (e.g. response according to the number of active agents in the OBR). Future studies may demonstrate that VCV is yet another CCR5 blocker with promising efficacy. Another 48-week study of a new drug in naïve patients that generated great interest was a study of the integrase inhibitor raltegravir.10 Antiretroviral-naïve patients (n=198) were randomized to receive either raltegravir at one of four different doses BID (100 mg, 200 mg, 400 mg, or 600 mg) vs. EFV 600 mg daily, all with a backbone of tenofovir 300 mg daily and 3TC 150 mg BID. Baseline characteristics were also similar for all patients. All patient groups experienced >2.2 log10 viral load decreases with similar increases in CD4+ cells. Patients receiving raltegravir achieved a viral load <50 copies/mL sooner than patients on EFV, but by week 24 and through week 48 the virological responses were similar. Drug related adverse events were similar for all groups except for the well-known association of central nervous system adverse effects with EFV. Also, there were elevations in total cholesterol and triglycerides for EFV but not for raltegravir. Thus, it can be concluded that raltegravir seems to be an efficacious and well-tolerated drug in naïve patients with an efficacy and safety profile comparable to that of EFV. TMC-125 (etravirine), a novel NNRTI, is also undergoing intensive clinical testing. Two studies identical in design and different only with respect the region of the world where they were conducted (DUET-1 [n=612] and DUET-2 [n=591]) were presented at the conference.11,12 Patients with documented NNRTI resistance and >3 PI mutations were randomized to receive TMC-125 vs. placebo plus DVR/r plus investigator-chosen NRTIs ± enfuvirtide. A 24-week (out of a planned 96-week study) efficacy analysis was presented for each of the two studies (Table 3). The incidence of adverse events and toxicity-related treatment discontinuations were similar for both groups in both studies. The authors concluded that TMC-125 is the first NNRTI to show efficacy in patients with NNRTI resistance as well as being well tolerated and safe. Viral hepatitis Studies dealing with viral hepatitis are an important component of these international conferences, especially for correctional health care providers. However, not as many studies were presented on this topic at this particular conference; nonetheless, a few abstracts contained interesting observations and are worth noting. Most hepatitis work in recent years has focused on hepatitis C virus (HCV) since the rates of co-infection with HIV are so high. As there has been an effective vaccine for hepatitis B virus (HBV) for the last two decades, the number of HIV/HBV co-infected patients is not as large, but these patients are seen among our clinic populations and frequently pose a therapeutic challenge. An issue that complicates the management of HBV-HIV co-infection is the fact that patients may require treatment for HBV but may still have high CD4+ cell values and low HIV viral loads making treatment for HIV unnecessary. Thus, the use of agents for HBV but with activity against both viruses (e.g. lamivudine [3TC], and emtricitabine [FTC]) may lead to the selection of resistance by HIV against these agents. At a hepatitis symposium, Vicente Soriano from Madrid presented a useful algorithm for the treatment of HBV in patients who do not yet require treatment for HIV (Figure 3).13 Although the algorithm is based on expert opinion and would obviously need to be individualized for any particular patient, it is a potentially useful tool for the management of these patients. An issue that many HIV clinicians deal with frequently is diminished vaccine efficacy because of a compromised immune response. It has been clearly demonstrated that response rates to HBV vaccination are lower among HIV-infected individuals compared to those without HIV infection. Bortan and colleagues reported a retrospective study on the vaccination with recombinant HBV vaccine of HIV-infected individuals with either the standard dose (10 mcg at 0, 1, and 6 months) or a higher dose (40 mcg at 0, 1, and 6 months).14 Although the number of patients in the study was relatively small, the results were impressive: only 26% (11 of 42) of standard dose-vaccinees developed anti-HBs titers >10 IU/L whereas 82% (9 of 11) of high dose-vaccinees developed these titers. The standard and high dose vaccinees had similar CD4+ cell counts (398 and 353, respectively) and use of ART (88% and 91%, respectively). The investigators could not identify by multivariate analysis any factors (other than vaccine dose) that were associated with an adequate anti-HBs response. These results suggest that it is possible to successfully vaccinate HIV-infected individuals against HBV infection, although a larger study would be needed in order to establish the optimal dose. In general, the efficacy of treatment for HCV is disappointing with long-term sustained virologic response (SVR) rates as low as 20-30% especially among patients with HCV genotypes 1 and 4. A small retrospective study from Italy suggests, however, that even in the absence of SVR there might be a significant benefit to pegylated interferon (peg-IFN) and ribavirin (RBV) treatment.15 Twenty-five co-infected patients treated with peg-IFN and RBV for a median of 9 months but without SVR were compared to 25 co-infected and untreated patients matched for age, gender, and Child-Pugh score. After a median of 54 months of follow-up, 16% (n=4) of treated and 52% (n=13) of untreated controls, respectively, developed a study endpoint (death or development of ascites, jaundice, encephalopathy, gastrointestinal bleeding, or hepatocellular carcinoma) (p=0.02). By multivariate analysis the predictors of development of a study endpoint were use of peg-IFN therapy (adjusted RR=0.03; p=0.016) and the presence of detectable HIV RNA (adjusted RR=35.98; p=0.024). Thus, there seems to be benefit to therapy for HCV in co-infected patients - even in the absence of viral suppression. Resistance and tropism testing An observation regarding resistance testing with useful practical consequences was made by a group of British investigators.16 They retrospectively studied the outcome of genotypic testing (GT) in viral load samples with <1000 copies/ml vs. >1000 copies/ml from patients on antiretrovirals with either viral failure (a viral load <50 copies/ml followed by two HIV RNA levels >50 copies/ml) or failure to suppress (HIV RNA level >50 copies/ml after being on HIV therapy for >6 months). All 66 samples with a viral load >1000 copies/ml could be amplified and sequenced; remarkably, 56 of 67 (85%) of samples with a viral load <1000 copies/ml could also be amplified and sequenced. This was the case with both low (200-1000 copies/ml) (38 of 42 samp les; 90% success rate) as well as very low (50-200 copies/ml) (18 of 25 samples; 72% success rates) viral loads. This suggests that GT can identify the selection of resistance mutations at HIV RNA levels that are much lower than what has been thought possible up until now. The appropriate use of CCR5 receptor blockers will be dependent on the identification of the exact tropism of HIV. Use of CCR5 blockers on virus that expresses the CXCR4 receptor exclusively (X4 virus) or both CCR5 (R5 virus) and CXCR4 receptors (dual or mixed [D/M] populations) would not only be associated with decreased efficacy of CCR5 blockers but could lead to the selection of resistance to the other drugs in the regimen. There is a Food and Drug Administration (FDA)-approved phenotypic assay of tropism (Monogram Biosciences' Trofile) with a turnaround time and cost similar to that of the same company's Phenosense assay. In order to improve turnaround time and cost, several genotypic assays for tropism have been developed. These assays determine the genetic sequence of the V3 loop of gp120 (responsible for tropism) that is then matched through a variety of methods (position scoring matrices, neural networks, position-based rules, etc.) to actual tropism phenotypes. A prediction of tropism is thus generated. Low, et al. reported a study in which 920 V3 genotypes were analyzed by six different methods and the predicted tropism was then matched to the Trofile phenotype.17 The goal of the study was to determine the sensitivity and specificity of the genotypic methods. The sensitivity of ranged from 22-50% and the specificity from 88-97% leading the authors to conclude that these methods are not yet adequate for predicting the X4 phenotypes upon which the determination of the presence of D/M populations is made. Thus, our ability to accurately predict tropism by genotypes will be currently limited for now. Conclusions This international conference, conducted half way around the planet, yielded data that are useful in our real world management of HIV and associated conditions. Studies of existing antiretrovirals help us refine our use of these medications while trials of newer therapies raise the prospect of continued opportunities for improving the well-being of our patients. References: 1.Valdez-Madruga J, Berger DS, McMurchie M, et al. Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naïve, treatment-experienced patients: a randomized, controlled phase III trial (TITAN). [Abstract TUAB101]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 2.De Meyer S, De Paepe E, Vangeneugden T, et al. Effect of baseline and on-treatment mutations on the antiretroviral activity of darunavir/ritonavir (DRV/r) and lopinavir/ritonavir (LPV/r): results of a randomized, controlled, phase III study (TITAN). [Abstract WEPEB038]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 3.Mallal S, Phillips E, Carosi G, et al. PREDICT-1: a novel randomized prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). [Abstract WESS101]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 4.Marin B, Thiebaut R, Rondeau V, et al. Association between CD4 and HIV RNA with non AIDS-related causes of death in the era of combination antiretroviral therapy (cART). [Abstract WEPEB019]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 5.Emery S, SMART Study Group and INSIGHT. Major clinical outcomes in patients not treated with antiretroviral therapy (ART) at baseline in SMART; a rationale for a trial to examine early treatment of HIV diseases. [Abstract WEPEB018]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 6.Van Sighem, Gras L, Smit C, et al. A CD4 threshold below 350 cells/mm3 for starting HAART is associated with a higher risk of disease progression. [Abstract WEPEB016]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 7.Lichtenstein K, Armon C, Moorman A, et al. Initiation of antiretroviral therapy at higher CD4+ T cell counts reduces incidence of nucleoside analogue toxicities acutely and risk for later development with continued use of these agents in the HIV outpatient (HOPS) cohort. [Abstract MOPEB016]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 8.Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study. [Abstract WESS104]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 9.ACTG 5211; phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48 week results. [Abstract TUAB102]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 10.Markowitz M, Nguyen B-Y, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment of HIV- infected patients: 48-week data. [Abstract TUAB104]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 11.Mills A, Cahn P, Grinsztejn B, et al. DUET 1: 24-week results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients. [Abstract WESS204:1]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 12.Katlama C, Campbell T, Clotet B, et al. DUET 2: 24-week results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients. [Abstract WESS204]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 13.Soriano V. Hepatitis co-infection - not as easy as A, B, C. [Abstract MOBS104]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 14.Bortan A, Shah S, Epstein M, et al. The efficacy of high-dose hepatitis B vaccination in HIV-infected individuals. [Abstract MOPEB055]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 15.De Bona A, Galli L, Gallotta G, et al. Rate of cirrhosis progression reduced in HIV/HCV co-infected non-responders to anti-HCV therapy. [Abstract MOPEB049]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 16.Tong W, Chrystie I, Aboud M, et al. Usefulness of genotypic resistance tests (GRT) in patients with HIV-1 viral loads (VL) less than 1000 copies/ml [Abstract TUPEB031]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. 17.Low A, Sing T, Chan D, et al. Improving HIV genotyping algorithms for the prediction of X4 co-receptor usage in clinical isolates. [Abstract WEPEA005]. 4th International AIDS Society Meeting, July 22-25, Sydney, Australia. |
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