The Body Covers: The 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment
The Body's HIV Experts Discuss IAS 2003
Upon their return from Paris, The Body Pro asked its medical faculty what they felt was the most important research presented at the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Their responses appear below.
Trizivir-Only Therapy: ACTG 5095 Results Limit Its UsePaul Sax, M.D.: The data presented on NRTI-only therapies -- i.e., ACTG 5095 (Abstract 41) and the case series on high rates of virologic failure in patients on ABC/3TC/TDF-containing regimens (Abstract 43) -- have important implications for choosing initial therapy. ACTG 5095 was a well designed, randomized, double-blind trial that gave us new information about triple NRTI-based therapy, including: 1) virologic failure was more likely on NRTI-only regimens regardless of baseline viral load; and 2) even after achieving <50 copies/mL, virologic rebound occurred more commonly in the NRTI-only regimens than in efavirenz (EFV, Sustiva)-treated patients.
These results do not exclude using the Trizivir formulation for difficult-to-treat patient populations who otherwise have no options for therapy, or as part of a salvage regimen using more than three drugs, but we must conclude from these studies (and the now-terminated ELATE study comparing ABC/3TC/TDF to AZT/3TC/efavirenz) that NNRTI- or PI-based regimens are clearly preferable to NRTI-only approaches.
Trizivir-Only Therapy: Still Beneficial for the Hard-to-TreatJudith Aberg, M.D.: I think most people attending the conference would choose the results of ACTG 5095, which demonstrated that Trizivir alone is inferior virologically to efavirenz-containing arms. But, since I love controversy, I think the data presented by Drs. Tashima (Abstract 57) and Kumar (Poster 709) are worth critical review as well.
In their study, Trizivir was compared with Combivir (AZT/3TC)/nelfinavir (NFV, Viracept) and d4T (stavudine, Zerit)/3TC (lamivudine, Epivir)/nelfinavir. Virological response was similar across the groups, with proportions <400 copies/mL (intent to treat, M=F/observed on treatment) of 91%/48%, 89%/48% and 88%/44% for groups 1, 2 and 3, respectively. The mean CD4+ T-cell increase at 96 weeks was 265, 270 and 289 cells/mm3 for groups 1, 2 and 3, respectively. The mean absolute CD4+ T-cell count at 96 weeks was 619, 625 and 643 cells/mm3 for groups 1, 2 and 3, respectively. The proportions of subjects with HIV viral loads <50 copies/mL (intent to treat, M=F/observed on treatment) were 41%/78%, 39%/72% and 33%/66% for groups 1, 2 and 3, respectively.
In those patients with HIV viral loads >100,000 copies/mL at entry, the proportions of subjects achieving HIV viral loads <50 copies/mL (intent to treat, M=F) showed a similar pattern of response with 53% (Trizivir), 42% (Combivir/nelfinavir) and 29% (d4T/3TC/nelfinavir). Women tended to have less of a virologic response than men. In addition, the response rates for Trizivir were consistently higher in Hispanics (HIV RNA <400 copies/mL, 65%, 45%, 44%; HIV RNA <50 copies/mL, 61%, 39%, 31% for groups 1, 2 and 3, respectively).
So I guess I still question whether there is a sub-population who may benefit from Trizivir alone, even given the results of ACTG 5095, CNA 3005 and CNA 3014. All doctors wind up choosing one regimen over another based upon the individual patient; if we didn't, we'd all be prescribing the same regimen -- the one we believe to be the most potent for everyone. I can think of several patients I am currently treating who prefer to stay on Trizivir alone, are doing well clinically and have undetectable viral loads. Trizivir alone may not be optimum compared to other regimens, but for some individuals it may be their best option at this time.
Lipoatrophy Reversal Appears Possible; Atazanavir Data ImpressiveCal Cohen, M.D., M.S.: Since others have focused on the issues of initiation with triple-NRTI regimens, I'll focus on other aspects of the data presented. First, it was reassuring to see that it is possible to reverse lipoatrophy while maintaining viral suppression, as reported in the MITOX study (Abstract LB18). Patients in this study who stayed on abacavir (ABC, Ziagen) instead of AZT (zidovudine, Retrovir) or d4T showed continued improvement in lipoatrophy. This is the only study that has found this to be the case.
In addition, new data on atazanavir (ATV, Reyataz) was widely discussed because it raised the profile of this drug from less than impressive to meriting attention. Upon re-analysis of alternative samples (from different tubes) in the naive study, the data showed that the percentage of patients with viral suppression was comparable to that in studies of efavirenz. This was reassuring, as it confirmed our expectations of higher viral suppression rates for both efavirenz and atazanavir. That, in addition to the very surprising results showing that "boosted" atazanavir was similar to Kaletra (lopinavir/ritonavir) with regards to efficacy in PI-experienced patients (Forum 118), elevated atazanavir to a level similar to its peers when considering boosted PIs. While every drug has its pros and cons, atazanavir has some characteristics that make it distinctive -- particularly its lack of lipid effects, its low pill burden and once-daily dosing, whether boosted or unboosted. It is reasonable to predict much greater interest in this antiretroviral as a result of the data presented here.
Is There Still Hope for Structured Treatment Interruptions?Robert Frascino, M.D.: The most interesting research presented at the IAS 2003 meeting? Assuming that the comments by Nelson Mandela do not qualify as "research," I would agree that the data from ACTG 5095 are going to have the greatest and most immediate impact on clinical practice. It will also prompt the revision of guidelines currently recommending the use of Trizivir as sole therapy. Regimen modification or intensification may well be necessary for patients on the triple-NRTI pill post-ACTG 5095. Since the details and potential ramifications of this trial have been addressed by others, I'll focus on another common clinical dilemma where scientific research is hopefully redirecting clinical practice: treatment interruption.
Additional information from the CPCRA 064 study was presented by Dr. Jody Lawrence (Forum 119). It unequivocally indicated that HIV-infected patients experiencing treatment failure do not benefit either immunologically or virologically from structured treatment interruptions (STIs), regardless of their baseline CD4 count or phenotypic sensitivity score. This was a randomized study of 270 patients with HIV RNA levels greater than 5,000 copies/mL. Subgroup analysis based on immune status and sensitivity of virus to drugs in the baseline regimen showed that during a 12-month follow-up, all patient subgroups randomized to treatment interruption had worse mean CD4 count responses when compared to those who had no break in treatment.
Turning now to treatment interruption during acute seroconversion. Dr. Bruce Walker reported on the extended follow-up of 14 people who all began treatment before full seroconversion and then suspended therapy one or more times (Forum 12). The hope was for immunological benefit prompted by these breaks; however, 11 of the 14 people failed to control HIV after interrupting treatment begun during primary infection. The results of this small non-randomized study do not show any clinical benefit of treatment interruption during acute seroconversion.
There were approximately 15 abstracts dealing with treatment interruption presented at the 2nd IAS meeting. Some were prospective studies of planned interruption; however, many were observational evaluations of patients who had already discontinued their medications. Criteria for discontinuation and reinitiation varied in the different trials. Some patients were able to stay off therapy for a period of time; in others, significant drug resistance and immunological deterioration were noted. The potential downsides to treatment interruptions include development of resistance, acute retroviral syndrome and increased risk of viral transmission while off therapy. The general consensus is that treatment interruptions have not been shown to be effective for specific purposes, such as autoimmunization or restoration of wild-type virus in the setting of treatment failure.
In clinical practice, treatment interruptions and intermittent therapy are popular and are being used more frequently. The weight of evidence presented recently would indicate that the use of STI for people chronically infected is not helpful and may have significant deleterious effects. Chronically infected HIV-positive individuals considering STI should be made aware of these potential risks.
The biggest question remaining now is whether or not treatment interruptions should be considered for people who were started on therapy at high CD4 counts. Current guidelines do not encourage antiretroviral therapy for those with CD4 cell counts above 350. Does continuing HAART therapy above this level increase drug toxicity risk without providing clinical benefit? We await the results of large clinical trials currently in progress to definitely answer this question. At this point, the best we can say is that long-term HAART has proven itself to be highly effective immunologically and virologically, if it can be tolerated. And finally, discontinuing effective HAART therapies carries very significant risks.
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