The 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) was held in Boston from February 27 to March 2, 2011. The CROI is a scientifically focused meeting where more than 4000 leading researchers (registration is limited to those actively participating as investigators in basic science or clinical studies) gather to translate laboratory and clinical research into progress against the HIV/AIDS epidemic.
For those not attending the conference, the official website (http://retroconference.org/2011) offers virtual coverage including audio (with mp3 downloads), video, and slides of all the plenary sessions, oral abstracts, themed discussions, and symposia. In addition, highlights of the CROI 2011 can be found at numerous other websites such as www.aidsmap.com, www.clinicaloptions.com, www.medscape.com/HIV, http://cfar.globalhealth.harvard.edu, www.thebody.com, www.hivandhepatitis.com, www.poz.com, and others.
This year, more than 1000 oral (1-173) and poster (174-1084) abstracts were accepted and printed in the program. The following is a sampling of some of the more interesting results.
Both the 2011 Department of Health and Human Services (www.aidsinfo.nih.gov) and European AIDS Clinical Society (www.europeanaidsclinicalsociety.org) guidelines state that abacavir should be used with caution in patients with high risk of cardiovascular disease. These recommendations were based in part on results of the Data Collection on Adverse Events of Anti-HIV Drugs cohort and the Strategies for Management of Anti-Retroviral Therapies studies; however, other data sets have found no such association. Further confusing the picture, the Food and Drug Administration reported in abstract 808 (Ding X. et al) that their meta-analysis of randomized trials found no significant difference in frequency of myocardial infarction between patients receiving abacavir-containing regimens versus non-abacavir-containing regimens.
Raltegravir is marketed as a twice-daily antiretroviral. Because of its long intracellular half-half and the potential for better adherence, the once-daily Rategravir in Treatment-Naïve Paris trial was performed. It was a randomized phase 3 study comparing once-daily with twice-daily raltegravir in treatment-naive patients. Unfortunately, the experimental once daily regimen, while quite active, did not measure up to giving the drug twice daily (Eron J. et al, Abstract 150LB). In another disappointing treatment-naive raltegravir study (Babafemi T. et al, Abstract 551), pairing it with ritonovir-boosted darunavir in a nuke-sparing regimen (ACTG A5262-single arm study) was associated with more virologic failure and integrase resistance in patients with a baseline viral load greater than 100,000 copies per milliliter.
Tenofovir has been linked to increased bone loss over time as evidenced by elevated levels of parathyroid hormone, decreased bone density, and reduced renal tubular phosphate absorption. Abstract 80 (Havens P. et al) reported the results of vitamin D3 supplementation in human immunodeficiency virus (HIV)-infected adolescents being treated tenofovir-containing antiretroviral therapy. The 12-week course of high-dose vitamin D3 (50,000 IU every 4 weeks) was safe and significantly reduced both vitamin D insufficiency and PTH levels.
The last antiretroviral agent to be Food and Drug Administration approved was the second-generation non-nucleotide reverse transcriptase inhibitor, etravirine (formerly TMC125, the nomenclature first applied to the drug before it was given a name, and marketed as Intelence), in January 2008. In Abstract 152LB (Markowitz M. et al), data were presented on a new prodrug (GS-7340) of tenofovir. GS-7340 can be given once daily and delivers high concentrations of tenofovir diphosphate to lymphoid cells (but with lower systemic drug levels, thus with the potential of fewer systemic adverse effects). No resistance or unique adverse effects were identified in this small, manufacturer-sponsored trial in treatment-naive patients.
The integrase inhibitor family is expanding from raltegravir and elvitegravir (GS-9137) to the newly named dolutegravir (DTG, formerly S/GSK1349572 or just "572"). Dolutegravir demonstrates excellent virologic activity in both treatment-naive and treatment-experienced patients (including among raltegravir-induced integrase-resistant viruses [Eron J. et al, Abstract 151LB]); twice-daily dosing was associated with a significantly greater mean reduction in viral load than once-daily dosing.
The first-in-class attachment inhibitor, BMS-663088, targets HIV by binding directly to HIV gp120; this agent joins enfuvirtide (fusion inhibitor) and maraviroc as entry attackers of HIV. In Abstract 49 (Nettles R. et al), results of a dose-ranging study of BMS-663088 (with 4 of 5 doses boosted with ritonovir) were presented. The drug was well-tolerated and decreased viral load by a median of 1.64 log copies per milliliter. BMS-660388 had better outcomes with ritonovir-boosting and twice-daily dosing.
HIV AND COINFECTION
Tuberculosis remains the number one cause of HIV/AIDS deaths globally. Abstract 38 (Havlir D. et al) added further support for initiating ART in patients with advanced immunosuppression (CD4 counts <50 cells per cubic millimeter) no later than 4 weeks after the start of antituberculosis therapy. Despite increasing the risk of immune reconstitution inflammatory response, the risk is outweighed by the survival benefit and the reduced risk for further clinical acquired immunodeficiency syndrome (AIDS)-defining conditions.
Human immunodeficiency virus and hepatitis C virus coinfection is a complex therapeutic problem requiring the use of peginterferon and ribavirin. However, the first 2 HCV-protease inhibitors-telaprevir and boceprevir-are expected to be approved this summer, and the therapy of HCV will become more effective but also more complicated. Potential drug interactions were reported in abstracts 118 (Kasserra C. et al) and 119 (van Heeswijk R. et al) and included (1) reduced levels of both protease inhibitors with efavirenz; (2) near-doubling of atazanavir Cmin with concurrent telaprevir and; (3) worrisome interactions of telaprevir with boosted darunavir, lopinavir, and fosamprevanvir. Telaprevir added to peginterferon/ribavirin-achieved rapid virologic response in 70% of patients compared to only 5% of patients in the placebo arm (Sulkowski M. et al, Abstract 146LB).
(An excellent downloadable slide set by Dr. Stefan Zeurem reviewing all the direct-acting anti-HCV agents, including protease inhibitors, nucleoside, and nonnucleoside polymerase inhibitors, and NS5A inhibitors is available at www.clinicaloptions.com/hepatitis/treatment).
The use of pre-exposure prophylaxis (PrEP) has been addressed in several studies the past several years. Initial proof-of-concept trials have shown moderate effectiveness for both topical (microbicides, etc) and oral PrEP. There is a strong correlation between adherence and effectiveness. Pre-exposure prophylaxis received a fair amount of attention at CROI 2011. In general, it works if you take it. In the pre-exposure prophylaxis as HIV prevention among men who have sex with men study (Amico R. et al, Abstract 95LB), participants took daily oral emtricitabine/tenofovir as PrEP; the absence of study drug in the bloodstream was a strong predictor of HIV acquisition. Another novel and reliable biomarker of PrEP adherence was the level of tenofovir in scalp hair (Liu A. et al, Abstract 995). Cost and safety are major concerns with PrEP. In the global iPrEx study using Truvada in HIV-negative men who have sex with men, there were small but significant decreases in bone mineral density in those randomized to Truvada. There are numerous other studies ongoing. More data are needed before physicians prescribe PrEP in most situations.
As children with AIDS age into adulthood, they will be increasingly seen is adult clinics. Abstract 82LB (Simard E. et al) reported that childhood AIDS increases cancer risk (eg, Kaposi sarcoma, non-Hodgkin lymphoma, and leiomyosarcoma) later in life. Therefore, long-term monitoring will be important. Abstract 769 (Drake A. et al) concluded that valacyclovir suppressive therapy in women coinfected with both HIV-1 and herpes simplex virus (HSV)-2 significantly decreased plasma HIV-1 RNA levels and HSV-2 genital shedding during pregnancy among women also receiving zidovudine prophylaxis for prevention of mother-to child transmission; thus, valacyclovir may block vertical transmission of HSV-2 if larger studies confirm the findings of this small pilot trial.
2011-30th Commemoration of HIV/AIDS.