STBBIs & the CTN

In 2008, about 20% of people living with HIV in Canada (13,127 people) were estimated to be also living with HCV. Compared to either HIV or HCV alone, management of HIV and HCV together is much more complex — timing of treatments, preventing drug interactions, and addressing the progression of liver disease are all vital components of clinical care for these people. First published 2013 and then updated in 2016, the CTN supported the development of Canadian Guidelines for Management and Treatment of HIV/HCV in Adults. These guidelines provide clinicians with an overview of the epidemiology, interactions, and best practices related to HIV and HCV. Eight of the ten authors who contributed to the Guidelines are CTN Investigators: Mark Hull (lead author), Stephen Shafran, Alex Wong, Lisa Barrett, Shariq Haider, Brian Conway, Marina Klein, and Curtis Cooper.

One of the co-authors of the Guidelines, Dr. Marina Klein, CTN National Co-director, leads a number of CTN studies in HIV-HCV. The largest of these studies, CTN 222, the first observational cohort study in the Network, follows over 2,000 Canadians living with HIV and HCV in 18 sites across Canada. To date, the CTN 222 team has published more than 35 articles, a body of work that provides insight into a variety of aspects of HIV-HCV coinfection, including risk factors for liver disease, treatment efficacy and adherence rates, and impacts and interactions of the viruses. This study also spawned a sub-study, CTN 264, which explored the risk factors and consequences of food insecurity in people living with HIV and HCV.

Another large observational cohort that involves people living with HIV and HCV is the Canadian Observational Cohort Collaboration (CANOC; CTN 242). This study combines nine cohorts from BC, Ontario, and Quebec into one large, integrated database—nearly 50% of Canadians living with HIV that have been on treatment since 2000 are included in CANOC. This wealth of information has allowed CANOC researchers to follow regional trends, track treatment outcomes and identify knowledge gaps. Because of the large number of participants in the cohort (13,000+), researchers are able to gather information about specific groups of people living with HIV, including those with HCV—multiple publications from this cohort relate to HIV-HCV coinfection.

The CTN has also supported several studies that test the impact of different treatment regimens on HIV and HCV. The Raltegravir Switch Study (CTN 260), was a pilot study funded in 2011 that assessed if switching from ritonavir boosted-protease inhibitor-based ART regimen to a raltegravir-based regimen could reduce the rate of hepatic fibrosis progression. Raltegravir has been shown to be healthier for the liver but has not been fully studied in people living with HIV as well as HCV.

The E/C/F/TAF Switch Study (CTN 289) investigated if switching ART regimens could reduce drug-drug interactions between HCV direct acting antivirals (DAA) and ART. Because of the relatively recent development of DAAs, there is little information about the interactions between these two types of drugs. CTN 289 showed that switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya; E/C/F/TAF) before starting ledipasivir-sofosbuvir (a DAA) is safe, feasible, well tolerated, and avoids drug–drug interactions while maintaining HIV suppression and generally curing HCV. This study is led by Dr. Curtis Cooper.

Dr. Cooper also led CTNPT 019, a pilot study that aimed to test the effectiveness of metformin, a treatment for type 2 diabetes, in preventing and improving liver fibrosis in people living with both HIV and HCV or HCV alone. Unfortunately, the study did not proceed as planned due to changes in treatment standards. The study was the primary focus of CTN postdoctoral fellow Mary-Anne Doyle (2013-15), supervised by Dr. Cooper.

Also in the data analysis phase is CTNPT 014, a pilot study led by Dr. Brian Conway that is examining the efficacy of treating HIV with a combination of lopinavir/ritanovir (Kaletra) with maraviroc (Celsentri). Because maraviroc may prevent scaring and fibrosis of the liver, investigators are testing it as part of a combination therapy to try to reduce negative effects on the liver and improve the subsequent treatment of HCV.

Several CTN Postdoctoral Fellows have focused on HIV and HCV for their projects:

• Dr. Nasheed Moqueet: Mathematical modeling of sexual co-transmission of hepatitis C and HIV in gay, bisexual and other men who have sex with men in Canada (2017-current; supervised by Drs. Sharmistha Mishra and Ann Burchell )
• Dr. Nadine Kronfli: Hepatic fibrosis progression in HIV/HCV co-infection: The effect of iron-deficiency anemia among co-infected women (2016-18; supervised by Dr. Marina Klein)
• Dr. Margo Pearce: Recognizing and responding to barriers to HCV treatment among young indigenous people who use drugs in two Canadian cities (2015-18; supervised by Drs. Marina Klein and Bob Hogg)
• Dr. Mary-Anne Doyle: Preventing the progression of liver fibrosis with metformin in HCV-HIV co-infected patients (2013-15; supervised by Dr. Curtis Cooper)
• Dr. Ade Odueyungbo: A randomized prospective open label pilot study of switching to Raltegravir based ART compared to maintaining ritonavir boosted PI-based ART on liver fibrosis progression in HIV/HCV co-infection (2010-12; supervised by Dr. Marina Klein)
• Dr. Martin Potter: Evaluation of the risk factors of the individuals with HIV+ HCV infection and their implication with regards to access to and success of HCV treatments, overall social and health status (2008-10; supervised by Drs. Marina Klein and Joe Cox)
• Dr. Nima Machouf: Design and analysis of clinical trials for persons dually infected with HIV and HCV. Use of observational databases to explore therapeutic, pathophysiologic and prognostic factors in the natural history of HIV infection (2002-04; supervised by Dr. Christos Tsoukas)

Before the advent of DAAs, acute and chronic HCV were treated with peg-interferon. An earlier study, CTN 141, which ran from 2000 to 2003 tested a combination of drugs for the simultaneous treatment of HCV and HIV; peg-interferon alpha, ribavirin, didanosine (ddl), and lamivudine (3TC). Both ddl and 3TC are HIV antiretrovirals and ribavirin is an HCV antiviral medication. Unfortunately, this study was stopped early because the USA Federal Drug Administration published a notice about the risk of toxicity when ddl and ribavirine are used in combination.

Another study which was terminated early due to regulatory issues was CTN 227, a study that was testing the use of an HCV therapeutic vaccine to treat people who had experienced a viral relapse after treatment with peg-interferon alpha and ribavirin.

Peg-interferon, although moderately effective, has a number of side-effects including flu-like symptoms, thyroid dysfunction, and depression. CTN 194, which ran from 2009–2012, tested the effectiveness of citalopram, an anti-depressant, in preventing the development of depression in people with HIV starting HCV treatment with pegylated interferon and ribavirin. Despite excellent adherence to the medication in the trial, no impact of citalopram on depressive symptoms was found.

Vaccination against HPV has been shown to reduce cervical infection and resultant precancerous disease in HIV-negative girls and women. Despite being disproportionately affected by HPV, data about HPV vaccinations in females living with HPV is limited. A study of an HPV vaccine in a cohort of HIV-positive girls and women (CTN 236), one of the first studies in the world to examine this question, is studying whether an HPV vaccine (Gardasil) works as effectively in people living with HIV compared to those without. The study, led by Dr. Deborah Money, has two phases: an initial short-term phase (2 years) and a long-term follow-up phase. Results from the initial phase demonstrated that the HIV-positive women (310 vaccinated participants) had strong immune responses to the vaccine, creating antibodies to protect against future infection at comparable rates to the HIV-negative population.

A second publication analyzing the same data in a cohort of girls aged 9-13 living with HIV showed that the vaccine was not as effective as in women; the immune response to the vaccine was lower compared to their HIV-negative peers in the girls in cohort. In both girls and women, virologic suppression of HIV predicted a stronger vaccine immune response. A follow-up paper published in the summer of 2018 demonstrated the vaccine’s efficacy over a two year period. The publication showed that the rate of HPV infection was greatly diminished compared to rates seen in unvaccinated women and girls living with HIV. CTN 236 is currently in the follow-up phase to examine long-term responses to the vaccine over an additional period of three years.

The high prevalence of high-risk anal HPV in men who have sex with men living with HIV puts this group at the highest risk of anal cancer (50-100 times higher than the general population). Several recent CTN studies have been funded to address the detection and treatment of HPV in these men. Dr. Troy Grennan leads the NOMAD Study (CTNPT 023) which examined the effectiveness, feasibility, and usefulness of a new test (mRNA-based HPV assay) to detect specific cancer-causing HPV. Two different aspects of this technique were studied: (1) the overall performance of the test with self-collected anal swabs and (2) compare the performance of self-collected versus clinician-collected sampling. Preliminary results presented at CAHR 2018 demonstrated the feasibility and sampling accuracy of self-collection with participants finding the intervention to be acceptable.

Dr. Grennan also leads the HPV-SAVE Studies, a set of two large studies that were funded in 2015. These studies have two aims: (1) to develop and validate an anal cancer screening algorithm in HIV+ MSM (CTN 292A), and (2) randomized controlled trials examining the efficacy, safety, and tolerability of ablative therapies for high-grade anal dysplasia versus observation alone in HIV+ MSM (CTN 292B). In this case, ablative therapies refer to the removal of the upper layers of cells of precancerous tissues with an instrument that burns the area. There is no long-term evidence that this type of treatment is effective. In combination, these studies will help to optimize our approaches screening, preventing, and treating HPV-related anal disease. Both studies are currently in the enrolling phase.

Dr. Grennan’s CTN postdoctoral fellowship (2011–2013) focused on comparing transmission rates of HPV between partners in HIV-positive and HIV-negative men. Another CTN postdoc, Alexandra de Pokomandy (2004–2007), looked at the impact of HPV in men living with HIV and the correlation between HPV viral load and immune status. Dr. Pokomandy found an extremely high prevalence of HPV infection (either active or cleared) in HIV-positive men in Montreal (97.9%). She also published a paper on the types of HPV and pre-cancerous cells and risk factors associated with HPV in HIV-positive men. Following her postdoc, Dr. Pokomandy led CTN 216, a study which tested the tolerability, safety, and efficacy of a surgical intervention (argon plasma coagulation) to prevent anal cancer. Results for this study were published in August of 2017 and found that this technique can be successfully used to treat pre-cancerous cells but it requires repeated treatment and long-term follow-up.

Much of Dr. Darrell Tan’s contributions to the CTN have been focused on the interaction and treatment of HSV-2 with HIV. As a CTN postdoctoral fellow (2007-08), Dr. Tan found that HSV-2 did not affect the decline in CD4 count in people with untreated HIV. Dr. Tan also found that, in people on stable ART, HSV-2 did not increase immune activation or inflammation. At the time of these studies, a consensus on the importance of early ART initiation had not been reached and people were not started on ART until their CD4 count dropped below a certain threshold. In keeping with this clinical strategy, treatments to delay the initiation of ART were being studied.

The VALacyclovir In Delaying Antiretroviral Treatment Entry Study (VALIDATE; CTN 240) enrolled 200 participants across 24 sites in Canada, the United Kingdom, Brazil, and Argentina. This multi-national trial was testing the impact of valacyclovir on HIV disease progression in treatment-naïve adults thereby delaying the need for ART initiation. Valacyclovir is a medication used to treat and prevent herpes HSV-2 which had been associated with decreased HIV viral load but had not been adequately tested. Results presented in poster format at CAHR and CROI in 2017 showed that, despite decreasing HIV viral load, no effect of valacyclovir was found on CD4 T-cell decline. These results were confirmed by a 2018 publication. CTN 240 was led by Drs. Darrell Tan and Sharon Walmsley.

Dr. Tan later led a pilot study (CNTPT 016: Herpesvirus shedding among HIV inpatients) whichenrolled people living with HIV who had been admitted to hospital with an acute illness or opportunistic infection and studied whether common viruses like HSV-2 and cytomegalovirus contribute to their hospital outcomes and length of stay without causing symptoms. The primary objective of this pilot study is to determine the feasibility of a larger clinical trial or drug intervention trial — the study is currently in the data analysis phase. Another pilot trial, CTNPT 017, also led by Drs. Darrell Tan and Sharon Walmsley, investigated whether valacyclovir could help reduce persistent inflammation in people living with HIV and HSV-2. Unfortunately, the treatment had no significant impact on systemic immune activation or inflammation in people living with HIV and HSV-2 taking antiretroviral therapy

Another study, CTN 254, led by Dr. Mark Hull aimed to understand the impact of inflammation on people who had yet to start ART, the impact of ART initiation on inflammation, and the impact of HSV-2 co-infection and treatment. This study followed people who were participating in CTN 240, discussed above, and CTN 238, a study which tested the impact of micronutrient and antioxidant supplements on HIV disease progression.

In a plenary talk at CAHR 2017, Dr. Ann Burchell stated that, in Ontario, 1 in 4 HIV-positive MSM have had syphilis, which is spread via a bacteria transmitted during sexual activity [these data were also published in BMC Infectious Diseases]. Syphilis increases the risk of contracting or transmitting HIV and can make HIV treatment more difficult. Between 2002 and 2014, 99.9% of HIV-syphilis co-infection in Ontario were in males. Dr. Burchell is leading a study (CTN 275; ESSAHM Trial) which is testing the feasibility, usefulness, and cost-effectiveness of improving syphilis screening among HIV-positive men by introducing syphilis screening as a part of regular HIV testing. The study will measure if the introduction of routine testing changes the rates of detection for new, untreated syphilis cases. The first of its kind in Canada, findings from this study could be applicable to how we detect and screen for other STBBIs and viral hepatitis. CTN postdoctoral fellow, Dr. Ronita Nath, who was supervised by Dr. Troy Grennan, investigated the attitudes, beliefs, and knowledge about sexual behaviours in MSM in an attempt to better understand the drivers of syphilis and other bacterial STIs.

Cytomegalovirus (CMV) is an extremely prevalent virus, present in an estimated 40-100% of people worldwide. In those with healthy immune function, the virus goes unnoticed and does not cause symptoms. However, in those with compromised immune systems (uncontrolled HIV, leukemia, newborns), the virus can cause health complications including gastrointestinal infections and neurological disorders (more information is available on the Government of Canada’s website). CMV is the most common congenital infection (occurring or present at birth) in the world and is most commonly transmitted via breast milk. CTN Postdoctoral Fellow Dr. Elizabeth McClymont is investigating the viral and maternal factors that affect the risk of vertical transmission and whether these factors are different between people living with and without HIV.

Discussed above, CTNPT 016 is looking at whether this virus can contribute to hospital outcomes during acute illness or opportunistic infection in people living with HIV. The treatment of CMV and related opportunistic infections in people with AIDS was the focus of CTN 074, a study which was launched in 1994. The study compared the efficacy and safety of four doses of ganciclovir (3 oral, 1 intravenous) on the progression of CMV retinitis (inflammation of the retina). The results of the study, presented at the AIDS Conference in Vancouver in 1996, showed that moderate doses of the study drug were well-tolerated by patients but not as effective as the high-dose, intravenous ganciclovir.

Although not directly related to non-HIV STBBIs, CTN 257 has provided a wealth of knowledge about how the immune system and gut respond to infection and ART. This study is an observational cohort, meaning participants are not required to take any medication, only complete questionnaires and provide blood samples with three optional rectal biopsies. Researchers in this study have looked at the similar states of chronic, low-grade inflammation induced by both CMV and HIV, how the immune system and metabolism adapts to CMV in similar ways to HIV, and how CMV impacts the liver to understand liver fibrosis in hepatitis, among other related areas.