Important note: Information in this article was accurate in January 2004. The state of the art may have changed since the publication date.
 |
|
Paul A. Volberding, M.D., University of California at San Francisco and William G. Powderly, M.D., Washington University conducted a review of literature and conference presentations on the important new findings in HIV. The review was presented as part of “Symposium: What’s Hot: Review of Recent HIV and ID Literature” at the 41st IDSA meeting held in San Diego this fall and is summarized in this article. Treatment Interruption in Patients Failing Therapy A recent study demonstrated that for patients who have multidrug-resistant HIV and who are about to start a salvage regimen, treatment interruption prior to salvage therapy is clearly inferior to an immediate switch to the new regimen [N Engl J Med. 2003 Aug 28;349(9):837-46]. However, there may be potential settings in which STI makes sense. Katlama and co-workers recently presented some data showing that there may be some benefit in terms of viral load and CD4 count with treatment interruption of shorter duration and more aggressive therapy post-STI. The most promising new drug this year is enfuvirtide, or ENF. The TORO-1 [N Engl J Med. 2003 May 29;348(22):2186-95] and TORO-2 [N Engl J Med. 2003 May 29;348(22):2175-85] studies published recently showed significant benefits of ENF at 24 weeks when added to an optimized background antiretroviral regimen, and these benefits appear to hold at 48 weeks [IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. LB02]. The percentage of patients receiving ENF who achieved a 1 log10 reduction in viral load at 24 and 48 weeks was 47% and 37% respectively. Good prognostic factors included a baseline CD4 count >100 cells/mm3, viral load <100,000 c/mL, previous exposure to <10 antiretroviral drugs, and >active drugs in the "optimized background" regimen. The response rate in the ENF arm was only 15% if none of these factors was present, compared to 80% if all 4 factors were present. Continuation of RTIs in Failing PI-Based Regimens Steve Deeks presented some interesting preliminary data from a small, uncontrolled, nonrandomized study at the CROI meeting this year [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 640]. As we know from clinical experience, patients sometimes seem to do relatively well on antiretroviral therapy despite ongoing viremia and extensive mutations that would predict virologic failure. This study attempted to identify the utility of selected individual drug therapy in patients who were failing protease inhibitor (PI)-based regimens by either discontinuing the PI or the nucleoside analog reverse transcriptase inhibitor (NRTI). Patients in whom the PI was discontinued did relatively well, with a trivial decrease in CD4 and increase in viral load. On the other hand, patients in whom the NRTIs were discontinued did poorly, with a rapid decline in CD4 count and rise in viral load. Although these data are very preliminary, and if confirmed in larger, controlled studies, they would suggest that at least in some patients failing PI-based regimens, the NRTI are still partially active and should be continued. At the IAS meeting, preliminary data on atazanavir (ATV) with and without ritonavir (RTV) boosting was presented. At 24 weeks boosted atazanavir appeared to be as potent, less lipotoxic, and more convenient in PI-experienced patients compared to lopinavir/ritonavir. Reduced Potency of Tenofovir/Abacavir Combination At the 2003 ICAAC meeting, data demonstrating the reduced potency of the combination regimen consisting of tenofovir, 3TC, and abacavir was presented [Gallant JE, et al. Abstract H-1722a 43rd ICAAC 2003, Chicago]. This regimen has been shown to lead to early virolgic failure compared to efavirenz, 3TC, and abacavir. However, the reason for the inferior potency of the triple nucleoside regimen is not known, since there are no data to suggest a drug-drug interaction (there is no apparent effect of tenofovir on serum abacavir levels), or intracellular interaction. Patients who received the triple nucleoside regimen were tested 12 weeks after initiation of therapy for drug resistance. Sixty-four percent (64%) of those who failed and had genotype data available had both M184V and K65R; 34% had only M184V. This suggests that this regimen may have a low genetic resistance barrier. Maternal-Fetal Transmission of HIV An important study appearing in the Lancet this year was the 18 month follow-up demonstrating the superiority of single dose intrapartum nevirapine to a short course of intrapartum/ neonatal zidovudine for prevention of maternalfetal transmission of HIV [Lancet. 2003 Sep 13;362(9387):859-68], in which nevirapine was shown to be superior to zidovudine in decreasing fetal HIV transmission. In addition to assignment to the zidovudine arm, predictors of increased neonatal transmission in this study included low maternal CD4 count and high maternal HIV RNA. Unfortunately, NNRTI-associated resistance mutations were eventually detected in up to 75% of patients receiving nevirapine. Markers Predicting Response to HAART Another study published in the Lancet looked at the effect of starting HAART on prognostic markers of HIV infection [Lancet. 2003 Aug 30;362(9385):679-86]. Previous data emphasized the importance of baseline CD4 and viral load on predicting long-term clinical outcomes, but this study concluded that once HAART was initiated, baseline CD4 and viral load were not as predictive of clinical outcome as was virologic response to HAART at 6 months. A study looked at the risk of developing cardiac disease on HAART [N Engl J Med. 2003 Feb 20;348(8):702-10]. This was a very large study of 36,799 patients followed at VA hospitals between 1991 and 1999, which found that the risk of cardiovascular events, including strokes, decreased over that time period. There was no evidence of an increase in cardiacrelated admissions with use of antiretroviral therapy (whether this was PI-based or not). These results are in contradistinction to an earlier and smaller study that demonstrated a relatively low, but increased risk of myocardial infarction (MI) associated with use of PIs (as well as with hypertension, tobacco use, male sex, age >50 years, dyslipidemia, and diabetes mellitus). The DAD study, a multivariate analysis of 13 studies that was presented at this year’s CROI, revealed an increasing risk of MI with longer duration of combination antiretroviral therapy [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 130]. Other independent risk factors included age, male sex, tobacco use, and cholesterol level. Unpublished data show that cholesterol levels actually fall after HIV seroconversion prior to initiation of HAART and then rise after HAART therapy. From all these data, however, it appears that the overall risk of cardiovascular disease remains relatively low and certainly does not justify not treating HIV if treatment is indicated. Clinical situations in which resistance testing is recommended include:
The CATCH study demonstrated that the prevalence of drug resistance in patients infected with HIV <1 year is ~11%, vs ~ 8% in those with chronic HIV (>1 year). Viral infectivity factor (VIF) is an HIV-1 accessory protein, that neutralizes a potent antiviral pathway in human T lymphocytes and is required for the production of infectious virions by CD4 lymphocytes. The cellular target of VIF was recently described in a series of papers [Nature. 2003 Jul 3;424(6944):99-103; Nature. 2003 Jul 3;424(6944):94-8]. VIF appears to counter the effect of APOBEC, a host cell cytidine deaminase nucleic acid-editing enzyme that inhibts retroviral replication by inducing hypermutation in the viral genome [Cell. 2003 Jul 11;114(1):21-31]. 20040101 ©1997-2004. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service. AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, Elton John AIDS Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2004. This material is designed to support, not replace, the relationship that exists between you and your doctor. AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV. Copyright ©1980, 2004. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.    |