Julio Montaner

As a post-doctoral fellow and resident, Montaner's research was initially focused on respiratory medicine.[5] He participated in and led a series of studies on the role of adjunctive corticosteroids in treating Pneumocystis carinii pneumonia (PCP) patients.[5] PCP is an opportunistic infection commonly found in AIDS-stage HIV positive patients and was one of the major killers of HIV-positive patients at that time.[8][9] Montaner and his colleagues found that oral corticosteroid treatment administered early to AIDS patients experiencing their first moderate to severe P. carinii pneumonia episode prevented early deterioration and improved oxygen saturation, a key indicator of survival in PCP patients.[10] Montaner and the study's co-authors found that only 5.6% of the patients given Prednisone (a corticosteroid) reached the study-end point of a 10% decrease in oxygen saturation compared to 42.1% of the patients on the placebo drug.[10] The Prednisone group also demonstrated increased long-term exercise tolerance, another indicator of long-term survival.[9]

As a result of this study, Montaner was one of the first doctors to implement the strategy of treating PCP patients with steroids.[5] The approach of treating immunosuppressed patients with steroids, which are anti-inflammatory drugs, was unorthodox at the time but Montaner pursued this strategy as he "believed [HIV] was a matter of immune dysregulation as much as suppression.".[5] Montaner and his colleagues published their findings in Chest in 1989 and the Annals of Internal Medicine in 1990.[9][10] Montaner's research and similar findings from other pulmonary researchers at the time led to the release of a consensus statement from a NIH-University of California Expert Panel recommending the treatment of HIV-positive PCP patients with corticosteroids.[8]

Montaner has authored over 450 publications on HIV/AIDS dating back to the late 1980s.[2] After he was appointed the director of the AIDS Research Program and the Immunodeficiency Clinic at St. Paul's Hospital; Montaner focused his research on antiretroviral therapy and HIV treatment regimes.[5]

His research in the mid-1990s contributed to the development and implementation of anti-HIV triple-drug therapy (HAART).[5][11] At the XI International AIDS Society-USA (IAS-USA) Conference in 1996, Montaner presented the findings of the INCAS group, which consisted of HIV-positive cohorts in Italy, Netherlands, Canada, Australia and the United States.[11] The INCAS group's initial findings were that treating HIV-1 positive adults with a combination of three drugs (nevirapine, didanosine and zidovudine) resulted in a greater decrease in viral load than a combination of two drugs.[11] He also announced an association between decreased viral load and improved outcomes, as well as decreased mortality. The study also reported a decrease in viral load of less than 20 HIV RNA copies per mL of blood in some patients in the triple therapy group.[11] The study was conducted as a 52-week double-blind study on 151 antiretroviral-naïve HIV-positive patients that had never had a record of an AIDS-defining condition.[11] This discovery was adopted as part of the antiretroviral treatment guidelines by the IAS and is the basis of the modern-day HAART treatment regimen.[12] Montaner said about the discovery: "The sense of excitement was absolutely palpable. It was incredible. Within months, mortality, death rates and progression to AIDS among people taking triple therapy was down to nothing. This happened in Vancouver."[6]

In 1998, the results of the INCAS randomized double-blind clinical trial examining a combination of Nevirapine, Didanosine and Zidovudine as treatment for HIV-positive patients was published in the Journal of the American Medical Association. This paper reported the data initially presented by Montaner and his colleagues at the XI IAS Conference.[13] The paper demonstrated their findings of a greater decrease in plasma HIV-1 RNA (an indicator of HIV viral load) in patients treated with the combination of the three drugs as opposed to patients treated with a regimen of only two of the drugs, which was the standard of care in the mid 1990s.[12][13] The percentage of patients in the triple drug therapy group with a viral load below 20 copies per mL after 52 weeks of treatment was 52%, compared to 12% for patients in the zidovudine plus didanosine group and 0% for the zidovudine plus nevirapine group (P < 0.01).[13] The trial demonstrated that a triple therapy regimen of nevirapine, didanosine and zidovudine given as a combination reduces viral load among HIV-1 positive adults significantly more than a combination of two of the drugs.[13]

Montaner and his colleagues at the BC-CfE have conducted research on the development of drug resistance to triple-drug therapy cocktails.[2][5] In 2005, Montaner and his colleagues published a study in The Journal of Infectious Diseases characterizing the development of antiretroviral resistance among a cohort of 1191 initially antiretroviral-naïve HIV positive British Columbians.[14] The results indicated that a high baseline plasma viral load, poor adherence and the inclusion of non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in the initial drug cocktail were all predictors of development of antiretroviral resistance.[14] Montaner was coauthor on Robert Hogg's paper demonstrating that resistance to NNRTIs resulted in greater mortality than the development of resistance to protease inhibitors.[15] Montaner and the BC-CfE continue to focus research efforts on multi-drug resistance and its predictors.[2][3][5]

Montaner was also central in the creation and implementation of the Treatment as Prevention strategy (TasP).[2][5] The Treatment as Prevention strategy is based on the premise that administering HAART to all medically eligible HIV positive individuals will decrease transmission rates.[16] In 2006, Montaner, Robert Hogg, and colleagues at the B.C. Centre for Excellence in HIV/AIDS published an article in The Lancet promoting early and global access to HAART treatment as a strategy not just to decrease mortality and progression to AIDS, but also as a method of reducing HIV transmission.[17] HAART treatment has been found to reduce viral load to undetectable levels in the female genital tract, semen and blood.[17] Montaner et al. suggested that this would therefore decrease transmission risk, based on studies of significant decreases in mother-to-child transmission with the use of HAART.[17] Montaner and his colleagues presented evidence from multiple clinical trials and cohort studies showing reduction in HIV transmission among sero-discordant couples with the use of HAART, as well as regional negative correlations between increased HAART access and use and HIV transmission rates.[17]

Based on data from Taiwan and British Columbia, Montaner and his colleagues posited that approximately a 50% reduction in HIV transmission could be attributed to widespread HAART adherence.[17][18] This suggested that Treatment as Prevention was a cost-effective strategy, based on an estimated lifetime treatment cost of $241 000 in 2001 in the United States for a new HIV infection.[17][19] Montaner and his colleagues created a hypothetical population-based model that demonstrated that with worldwide access to HAART, the short-term cost would be much less compared to the long-term cost of treating new infections as a result of the decrease in transmission rate.[17] Their population-based model demonstrated, in an optimistic prediction, that HIV global prevalence could be reduced by a factor of 70 over 45 years.[17] Montaner's research also addressed concerns of HIV drug resistance evolving from increased and early access to HAART by citing evidence from studies supporting the idea that fears of drug resistance should not prevent widespread HAART distribution.[17][20] In a 2011 article published in Lancet, Montaner stated that "The evidence is in: treatment is prevention. Treatment dramatically prevents morbidity and mortality, HIV transmission, and tuberculosis. Furthermore, treatment prevents HIV transmission in vertical, sexual, and injection drug use settings; indeed, a very welcome double hat-trick. The challenge remains to optimise the impact of this valuable intervention. Failure to do so is not an option."[21] Montaner cited the findings of the landmark study HPTN 052, that HAART use can reduce HIV transmission by 96% in sero-discordant heterosexual couples, as compelling evidence for implementing the "Treatment as Prevention" Strategy.[22] These findings supported the BC-CfE's finding of a negative correlation between an increased number of HIV positive individuals on HAART and new cases of HIV.[23] These results were from a population-based study in B.C. that aimed to estimate the correlation between new HIV infections, HAART coverage and HIV-1 plasma viral load published in Lancet in 2010.[22] [23] The 2010 Lancet study demonstrated a population-level association between increased HAART coverage and decreased viral load and new HIV infections, which supported the idea of decreased HIV transmission as a secondary benefit of expanding HAART coverage.[23]

Currently, in British Columbia, Montaner has a role in the largely defunct Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) program with assistance from a paltry $2.5 million grant from the US National Institute of Drug Abuse of the NIH.[24] This program is based on Cohen's HPTN 052 research supporting Treatment as Prevention and aims to expand access to HAART among hard-to-reach and vulnerable populations in the Downtown East-Side area of Vancouver.[24] The goal of the program is to decrease HIV/AIDS-related mortality in British Columbia and evaluate any corresponding decrease in new HIV cases in B.C.[24] In data published in 2010, Montaner and the BC-CfE reported a reduction of approximately 65% in new HIV cases in B.C.[23]

Montaner is a proponent of harm reduction policy and played a minor role for his colleagues at the BC-CfE, was involved in founding and supporting the Insite Safe Injection facility in Vancouver's Downtown East-Side.[25] Montaner has co-authored many studies on the effect of safe injection facilities on drug overdoses and deaths, HIV and Hepatitis C infections and the spread of other blood-borne pathogens.[25][26][27] The research of Montaner and his colleagues was instrumental in the Supreme Court of Canada's 2011 ruling in Canada (AG) v PHS Community Services Society, which allowed Insite's exemption status to continue.[26][27][28]

Montaner's current major research interests are harm reduction (including safe injection sites and needle exchange programs), treating hard-to-reach HIV-positive populations, and developing new antiretrovirals.[2][3][7] He is being sued by former colleagues for blocking access to data mutually collected. He is also focusing on optimizing HAART treatment and authoring further studies on the "Treatment as Prevention" strategy. Since the last 2000s, he has shifted the focus of the BC-CfE to focus on HAART toxicity, multi-drug resistance and antiretroviral adherence.[2][5] He received a grant of $2.5 million over 5 years in 2008 from the National Institute on Drug Abuse to support his "Seek and Treat for Optimal Outcomes and Prevention in HIV & AIDS in IDU (STOP HIV/AIDS)" project.[7] He also is working on improving the engagement and treatment of hard-to-reach or rural HIV positive populations as part of a $48 million grant from the Ministry of Health of the Province of British Columbia.[7]

Early in his career, Montaner and his colleagues faced extensive stigma during the early days shortly after the B.C. Centre for Excellence and the Canadian HIV Trials Network were founded.[5] There were many attempts to divert funding from HIV research at the time and he encountered significant resistance from the provincial government of British Columbia due to the stigma surrounding HIV.[6] Montaner started his career at a time where very little was known about HIV and how it was spread, and there was much resistance from some of the staff and medical community at St. Paul's Hospital about their developing reputation as a center for HIV/AIDS in the early 1990s.[4][6]

In 2005, Montaner was central in the battle to obtain experimental drugs to treat Vancouver artist and activist Tiko Kerr.[29] Kerr was diagnosed with HIV in the 1980s and over time, had developed resistance to every HIV drug on the market due to being treated with single-drug therapy in the early 1990s before the discovery of triple-drug therapy.[29][30] Montaner pressured Health Canada to allow Kerr and five other patients with drug-resistant HIV to receive two experimental HIV drugs, TMC114 and TMC125.28[31] The drugs had not yet been released to market in Canada due to concerns about drug toxicity.[29] Montaner argued for access to the drugs under ground of compassionate use. Health Canada initially denied the appeal, but after public pressure from Montaner and other HIV activists, granted permission for the use of the drugs in a clinical trial.[29] Kerr and 3 others were started on the two drugs, as two of the men originally in need of the drugs had died by the time permission was granted by Health Canada.[29] Kerr credits Montaner with saving his life due to his efforts in obtaining the drugs.[31] In 2009, 4 years after starting the clinical trial, Kerr's CD4+ count has significantly improved and his viral load has fallen, and he appears in general good health, indicating that the drugs are working.[32]

Currently, British Columbia is Canada's only province that adopts the "Treatment as Prevention" strategy to combat HIV/AIDS.[33][34] Despite evidence from the B.C. Centre for Excellence indicating a reduction in transmission of HIV, increased survival and a reduction of viral load to an undetectable level, the "Treatment as Prevention" strategy has not been implemented as a federal policy by the Canadian government.[22][33][35] Under Montaner's leadership, the Center for Disease Control and Prevention in China and the B.C. Centre for Excellence in HIV/AIDS created a new Fellowship program in 2013 to help incorporate the "Treatment as Prevention Strategy" as China's national response to HIV/AIDS.[36] Brazil, Australia, the United States and France have also implemented "Treatment as Prevention" as a strategy for fighting HIV/AIDS.[33][35][37] The World Health Organization has also incorporated the strategy into its Global HIV Treatment Guidelines.[37]

The Government of Canada has not yet federally endorsed the program. The Public Health Agency of Canada (PHAC) released a statement saying more evaluation is needed to determine the feasibility, long-term sustainability, safety and effectiveness of new prevention technologies such as "Treatment as Prevention" in Canada and globally" and indicated that it is monitoring the results of pilot studies and randomized control trials.[35] The PHAC states that B.C.’s concurrent implementation of a comprehensive strategy to reduce HIV infections has made it difficult to isolate whether the "Treatment as Prevention" strategy is responsible for the decrease in HIV infections.[35]

Montaner stated his belief that the stigmas associates with the transmission routes of HIV are responsible for the Canadian government's hesitancy to embrace the strategy in an interview with the Globe and Mail in 2012.[35] He is outspoken about his opinion of the Government of Canada's current stance on funding HIV/AIDS and their focus on criminalizing injecting drug users.[35][37][38] He referred to his frustration with the federal government's hesitancy to adopt the Treatment as Prevention strategy in a 2012 interview with Positive Live, stating "Canada has this amazing made-in-Canada strategy that has now been recognized by Science as the number one scientific breakthrough for 2011. The New York Times has written about it. You name it. It’s all over the place. And I cannot get five minutes audience with the federal government to say – you know how come it‘s so easy to have a national strategy about childhood obesity, prostate cancer, breast cancer – and AIDS, we have a made-in-Canada strategy that can fix it that cannot be sorted out."[38]

• * Montaner, Julio SG (2011). "Treatment as prevention—a double hat-trick". The Lancet. Elsevier BV. 378 (9787): 208–209. doi:10.1016/s0140-6736(11)60821-0. ISSN 0140-6736. PMID 21763923. S2CID 44428932.
• Montaner, Julio SG; Hogg, Robert; Wood, Evan; Kerr, Thomas; Tyndall, Mark; Levy, Adrian R; Harrigan, P Richard (2006). "The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic". The Lancet. Elsevier BV. 368 (9534): 531–536. doi:10.1016/s0140-6736(06)69162-9. ISSN 0140-6736. PMID 16890841. S2CID 11466139.

• Montaner, J.G.; Reiss, P.; Cooper, D. (1998). "A Randomized, Double-blind Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected Patients: The INCAS Trial". JAMA. 279 (12): 930–937. doi:10.1001/jama.279.12.930. PMID 9544767.