HIV/HCV Coinfection Remains Marginalized Despite Progress

The population of patients coinfected with HIV and hepatitis C in the U.S. remains largely marginalized for one reason or another. They are opioid drug users, Medicaid recipients, men who have sex with men; often, they are all the above. The fact that there are medications in the marketplace that can control or cure their dual infections makes their predicament even more frustrating. These are people who, clinically speaking, should be leading normal, healthy lives. Yet they are not.

Lianping Ti, PhD, a research scientist with the Epidemiology and Population Health program at the BC Centre for Excellence in HIV/AIDS and assistant professor in the Department of Medicine at the University of British Columbia, has focused largely on addiction. “You can’t understate that the over-prescription of opioids for pain has been a huge issue,” she said. “Trying to address the comorbid conditions of HIV, HCV and illicit drug use presents a host of challenges.”

Among the most important challenges is reinfection, according to Vincent Lo Re III, MD, MSCE, associate professor of medicine and epidemiology at the University of Pennsylvania. “The CDC and national and international societies need accurate and specific information to take the next steps toward hepatitis C elimination,” he said. “It is very important that we address hepatitis C treatment in high-risk subgroups to reduce the burden of liver disease, decrease hepatitis C transmission, and minimize hepatitis C reinfection after cure. These activities are crucial if we are to eliminate hepatitis C as a public health problem.”

With so many competing priorities, even successfully treating one of these patients can feel like an insurmountable task. Harm reduction programs need to be scaled up across the board, according to Ti. Surveillance and epidemiology of HIV/HCV coinfected populations and their associated comorbid conditions is essential, according to Lo Re. Access to HCV therapies remains problematic. Underlying all of this is a politically charged environment in which these patients rank lower than those with less stigmatized diseases.

Clinicians like Lo Re, who deal with these patients each day, see the reality of the impact of all this. “My patients are fearful and angry that they are being denied hepatitis C treatment,” he said.

But he continues to work, like so many others in the field — focused on specific obstacles and fighting the battle one patient and one issue at a time.

Safe Injection Habits

Horyniak and colleagues noted that incidence of coinfection among PWID are significantly lower in San Diego, Calif., than they are in Tijuana, Mexico, which lies just across the border. Baseline interviews and serologic testing data provided the study group with a wide range of information about the 567 study participants, including demographics, drug use habits, disease seropositivity and connections to and perceptions about Mexico.

Fifteen percent of the cohort reported recently crossing the border to inject drugs. However, no association was reported between crossing the border and HIV (OR = 0.85; 95% CI, 0.37-1.95) or HCV seropositivity (OR = 1.01; 95% CI, 0.62-1.65). Several factors reduced the likelihood of cross-border injection drug use, including age, identifying as Hispanic or Latino/a and concerns about violence when travelling to Mexico. Factors that increased cross-border drug use included at least weekly cocaine injection, having ever lived in Mexico and knowing PWID who reside in Mexico, according to the results.

However, needle sharing was lower among the individuals who used drugs across the border, as were equipment sharing and public injection (all P < .001). “Prevalence of HIV and HCV infection was similar among PWID who had and had not injected in Mexico, possibly due to practicing safer injecting while in Mexico,” the researchers concluded.

“We still need to understand better ways at harm reduction for patients who are actively using opioids, whether with syringe exchange alone or in combination with opiate agonist therapy,” Lo Re said. “This is crucial to reducing rates of injection drug use across the country.”

Lo Re also encouraged broader understanding of all facets of opioid use. “The FDA has recently taken steps in dealing with a form of extended release oxymorphone that appeared to contribute to the epidemic of hepatitis C and HIV in Scott County, Indiana,” he said. “Additional efforts are needed to stem the tide of opiate abuse.”

John T. Brooks, MD, a medical epidemiologist in CDC’s Division of HIV/AIDS Prevention, also cited the outbreak in Indiana as representative of the opioid epidemic in non-urban areas. “This population consists predominately of persons living in rural, often impoverished areas, which have limited prevention and treatment resources,” he said. “These rural areas may have little or no experience with HCV or HIV. As the 2015 outbreak in Scott County, Indiana demonstrated, when introduced into a rural network of injection drug users, HIV can spread explosively.”

Ongoing focus needs to be placed on HIV transmission among opioid users, according to Brooks. “The national increase in the number of persons newly injecting opiates threatens to erode our tremendous public health success controlling infections by this mode of transmission,” he said.

Campbell and colleagues wrote in a recent Morbidity and Mortality Weekly Report paper that in 2015, 17 states reported acute HCV incidence rates higher than the rate for the entire U.S. However, it was determined that only three states had statutes and Medicaid policies that would allow comprehensive prevention and treatment of HCV among injection drug users. They described types of laws and components of those laws that could reduce HCV transmission. The results showed that 18 states had laws defined as “least comprehensive” for preventing HCV transmission among PWID. Restrictive Medicaid treatment policies, including a necessary period of sobriety prior to treatment, were reported in 24 states. Sixteen states had no such sobriety requirements for Medicaid coverage of HCV therapy. Conversely, Maine, Nevada, and Utah had the most comprehensive laws for this purpose. Massachusetts, New Mexico, and Washington had comprehensive laws and permissive Medicaid policies.

The researchers concluded that creating and implementing state laws can be effective in reaching public health objectives to target a nationwide challenge such as the opioid epidemic. “This report can be used as a tool for states in establishing laws and policies to address increases in HCV incidence in their own jurisdictions, and as a source of data for evaluating the long-term impact of these laws and policies.”

Brooks brought the issue back to basics: “First, every patient with HIV needs to be tested for HCV,” he said. “Even though as many as 1 in 6 persons with HIV may be infected with HCV — and closer to 70% for persons who have a history of injecting drugs — CDC has estimated that almost 20% of patients who are receiving care for HIV infection have never been tested for HCV infection.”

It is also recommended that high-risk individuals like MSM or PWID should be re-tested annually, according to Brooks. “Being tested is the crucial first step to getting cured,” Brooks said. “Once diagnosed, we then need to ensure all patients have access to curative treatment as well as follow-up care to manage any complications that may be related to having had HCV infection.”

Reinfection in MSM

Hoorenborg and colleagues investigated HIV-negative MSM who initiated pre-exposure prophylaxis (PrEP) to determine rates of HCV prevalence. The study included 375 HIV-negative participants who enrolled in the Amsterdam PrEP demonstration project, 223 HIV-positive MSM, and 153 individuals from other at-risk groups besides MSM.

Results at enrollment showed that among the HIV-negative MSM, 4.8% (95% CI, 2.9-7.5) were anti-HCV and/or HCV RNA positive. Other findings indicated that 15 of 18 of these participants had detectable HCV RNA. Genotype 1a was reported in 73%, while 4d occurred in 20% and 2b occurred in 7%. All HCV-positive participants who were initiating PrEP were part of MSM-specific HCV clusters that included HIV-positive and HIV-negative MSM.

“HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported,” the researchers reported. “All HIV-negative, HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status.” The researchers recommended routine HCV testing for MSM at risk for HIV, including those who seek PrEP.

Making sense of data sets like this is about learning lessons from HIV and applying them to models in HCV, according to Ti. “There are similar transmission routes, even if the viruses, treatments, and cures are different,” she said. “One way to look at this is to export the treatment–as–prevention model. If we are treating individuals with safe, tolerable, shorter DAA regimens, the probability of transmission is reduced. But we need to understand that the higher the prevalence of chronic disease is in a certain setting, the more we have to scale up therapy.”

“There is concern about increasing incidence of HCV infection, even among MSM who use PrEP,” Lo Re said. “The downside of the success we have had with DAAs is reinfection, particularly among MSM and PWID.”

Lo Re noted that in the U.S., reinfection rates range from 2 to 6 per 100 person years among PWID and as high as 10 to 15 per 100 person years among HIV-infected MSM. Ti added that some areas of Canada are seeing reinfection rates higher than 20% in coinfected cohorts of MSM or PWID.

“There have been reports of clusters of sexually transmitted infection among MSM in North America and Europe,” Brooks said, and cited data from the CDC accrued between 2000 and 2013. “In contrast to other groups, such as heterosexuals and PWID, the rate of new HCV infection among MSM did not decline over time. There is no vaccine to prevent hepatitis C infection and details about how exactly hepatitis C is transmitted through sex are not well understood.”

The epidemiology is also poorly understood, according to Ti. “There isn’t really an understanding yet of other social structural services that impact reinfection,” she said. “The research being done here is to tease out rates of reinfection among certain populations. We don’t really understand the epidemiology around this because it is so varied in the literature.”

Lo Re picked up on this thread. “Surveillance for hepatitis C reinfection is crucial to better understanding this problem,” he said. “We need to determine the behavioral factors better. Interventions need to be developed and tested. In the setting of PrEP, we need to identify the factors associated with acute HCV infection among MSM to prevent rise of new infections.”

Accessing Treatment

A key component to the discussion of access pertains to the places where these patients receive care. Patients are often forced to receive opiate agonists in one place but no HIV therapy, or HIV treatment at one center but no DAA availability. In short, they are shuffled around, which generally increases the likelihood of dropping out of the system altogether.

Ti recommends an integrated care approach. “There has been some success with one-stop shopping as a way to reduce these patients shuffling around from provider to provider,” she said. “There has been a push in the community to collocate HCV treatment while addressing underlying risk factors. There are more and more centers that include HCV support groups, addiction treatment, access to HIV therapies.”

She noted that in British Columbia, the majority of coinfected patients are treated at HIV clinics, but acknowledged that provider-type restrictions often stand in the way. “Only gastroenterologists, ID specialists, or other physicians experienced with hepatitis C are allowed to prescribe DAA’s,” she said. “These prescriber restrictions are a limiting factor. As we move toward more comprehensive coverage, we are starting to see more treatment in the community from primary care providers. They are achieving similar success and SVR rates as specialists.”

Many experts believe a more fundamental shift in how these medications are prescribed is coming. “It could always be happening faster, but I think with that shift, the extra step of referring a primary care provider to a specialist to be linked to care will be removed, even among injection drug users,” Ti said.

The other aspect of restriction involves denial by payers among patients who fail to qualify based on fibrosis or cirrhosis scores.

“If we are going to eliminate this disease by 2030, we need to treat 260,000 patients yearly,” he said. “Understanding access to and coverage for treatment in real time is imperative to elimination efforts. Even though we have new drugs, and even though there’s competition in the marketplace, and even though we are starting to treat patients who don’t have advanced fibrosis and cirrhosis, we are still running into problems with insurers for reimbursement.”

This brings the discussion back to reinfection. “We are seeing that this integrated care model of achieving cure and reducing high-risk behaviors can reduce reinfection,” Ti said.

Current Political Climate

The health care debate at the level of the U.S. federal government has particular implications for this patient population.

“It is concerning because many of the plans that are being proposed are suggesting pretty severe cuts in services to Medicaid beneficiaries that will have very real and dramatic reverberations to all of the subgroups we are talking about, including MSM, opioid users, patients with chronic HCV, HIV and coinfected patients,” Lo Re said. He added that many patients in these groups are covered by state Medicaid programs. “I appreciate the challenges that are faced by our legislators but I think it’s prudent to consider the downstream effects of these changes for patients covered by health care exchanges or Medicaid.”

An added complication is that the situation is changing, seemingly, on a day-to-day or hour-to-hour basis, which makes it difficult for clinicians to prognosticate what will happen, and to plan treatment for individual patients. “What I really feel is the anxiety of my patients who are covered by these programs,” Lo Re said. “They are concerned about how they are going to get their health care, their medicines, the problems that may arise if they have no coverage. The fear is palpable.”

Of particular concern is the fact that many of the deliberations have not been transparent or been performed by committees as in the past, according to Lo Re. “Primary stakeholders such as insurers, patients and hospitals have not had the opportunity to adequately weigh in,” he said. But for all the frustrations and failures, Lo Re sees a glimmer of hope. “We are starting to hear a move for bipartisan discussions. If we are going to solve this country’s health care problems, we are going to have to work together. Hopefully, this will benefit our patients.”

Ti noted that Canada is looking to countries like Australia and France, which have offered universal access to HCV therapies. “Australia is having great success, treating everyone with HIV/HCV who has cirrhosis and liver disease progression,” she said. “They are now focusing on people who have F0 to F2 fibrosis.”

Canada recently secured a price negotiation with the pharma alliance to reduce the price of DAAs and expand access, according to Ti.

“By doing this, and by removing restrictions, we are seeing success as we move toward our goal of treating everyone by 2018 and 2019,” she said. “We are moving toward WHO goals. Most provinces have committed to removing restrictions to allow people with HIV and hepatitis B to be treated regardless of fibrosis score. It will be interesting to look at the impact of this policy shift on longer-term health care outcomes like HCC mortality.”

Clinical Factors

Kristen A. Stafford, MPH, PhD, assistant professor in the Division of Clinical Care & Research at the Institute of Human Virology, the Division of Genomic Epidemiology and Clinical Outcomes, and the Department of Epidemiology and Public Health at the University of Maryland School of Medicine, Mohammad Sajadi, MD, associate professor at the Institute of Human Virology at the University of Maryland School of Medicine, and colleagues conducted a single-center retrospective cohort study to determine the impact of HCV coinfection on complications and progression of HIV among 55 HIV elite controllers. HIV/HCV coinfection was reported in 45% of this group, while 55% were HIV mono-infected.

During a median 11 years’ follow-up, 25 patients experienced a complication, according to the findings. Other results showed that 16 patients lost elite control status. Complications in the coinfected group occurred at 4.78 times (95% CI, 1.5-15.28) the rate of the mono-infected group. This trend persisted in a multivariable analysis that controlled for factors including sex, injection drug use and older age. Cellular activation was higher in the HCV coinfected group, along with similar levels of lipopolysaccharide and soluble CD14. However, coinfection did not impact loss of elite control (HR = 0.75; 95% CI, 0.27-2.06). The researchers concluded that HCV coinfection may not directly impact replication dynamics or the natural history of HIV, but that synergy between the two diseases may create more complications such as cancer, cardiovascular disease, organ failure or death.

Sajadi and Stafford raised the simple question of whether coinfected patients do worse than mono-infected patients. “One way of looking at this question is whether the presence of HCV affects the natural history of HIV — if it leads to more rapid loss of CD4 cells, for example,” they wrote in an email to HCV Next. “We know that persons with HIV/HCV coinfection that are started on HAART have a slower initial CD4 rise but that this eventually equals those without HCV, so one question we had in this group of HIV elite controllers was whether HCV could affect the natural history of HIV infection. We found no evidence of this: there was no difference in CD4 rates of loss or loss of HIV elite controller status.”

The two researchers stressed caution when interpreting the observational data, largely because it was unknown whether HIV or HCV infection came first in individual patients. “We don’t have a picture of any changes or influence HCV might have had on HIV viral dynamics during seroconversion, or vice versa,” they wrote.

There may also be epidemiological implications to this research, according to the two investigators. “Unfortunately, we cannot observe the people in this cohort both infected and uninfected at the same time over the same time period with all other attributes held constant,” they said. “By looking at this question of HIV/HCV coinfection and its association with the development or complications and loss viral control among a group of HIV elite controllers, we were able to effectively control for one potential significant confounder. It has been epidemiologically difficult to parse out the effect of the drug regimens from the effect of the virus itself in treated cohorts. One of the opportunities we saw with this cohort was that it eliminated the potential effects that the antiretroviral regimens may have on the development of complications associated with immune activation and inflammation.”

The hope was to compare the impact of one virus with the impact of two in a group that was homogeneous regarding behavioral factors. “It is still difficult in this observational cohort to interpret these results in a purely causal framework,” they said.

With all of this in mind, the investigators suggested that the findings lead to the next logical question for research: “It will be interesting to see if this association persists among new identified natural viral suppressors with HCV coinfection now that HCV can be cured with DAAs,” they said.

Drug-Drug Interactions

The impact of chronic medications on HCV-related liver disease is also an important but understudied issue. Lo Re and colleagues have begun studying such associations in the setting of HIV infection. His team investigated the associations between the use of antiretroviral therapy containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) and liver decompensation in a cohort of HIV/HCV patients. The study included 1,747 HIV/HCV patients followed for 7,033 person -years between 2002 and 2009. Cumulative mtNRTI use yielded an increase in hepatic decompensation risk, with the risk generally increasing over time of treatment (1 to 11 months, [HR] = 1.79; 95% CI, 0.74-4.31), (12 to 35 months, HR = 1.39; 95% CI, 0.68-2.87), (36 to 71 months, HR = 2.27; 95% CI, 0.92-5.60), (>71 months, HR = 4.66; 95% CI, 1.04-20.83; P = .045) compared with patients who did not use these drugs. Mortality risk also increased with cumulative mtNRTI use over time (1 to 11 months, HR = 2.24; 95% CI, 1.04-4.81), (12 to 35 months, HR = 2.05; 95% CI, 0.68-6.20), (36 to 71 months HR = 3.04; 95% CI, 1.12-8.26), and (>71 months, HR = 3.93; 95% CI, 0.75-20.50); P = .03).

“These drugs should be avoided when alternatives exist for HIV/HCV patients,” the researchers concluded.

Lo Re also evaluated the risk of acute liver injury associated with statin use by HIV and chronic hepatitis C status. “Regardless of what acute liver injury endpoint we examined, statin use was associated with reduced rates of liver injury, regardless of HIV or chronic HCV status” he said.

Additional studies are needed to determine the impact of other chronic medications on liver disease in patients with chronic hepatitis C, he noted.

Smolders and colleagues conducted a retrospective, cross-sectional study using nationwide data from a Dutch database to describe the use of antiretroviral medications among coinfected patients and to further understand potential drug-drug interactions (DDI) between these drugs and HCV medications. The study included 777 patients accrued on Jan. 1, 2015. Among 488 patients who used non-antiretroviral co-medications, 38% were at risk for a category 2/3 DDI. Most of these events were predictable, and involved paritaprevir/ritonavir, ombitasvir ± dasabuvir (Viekira Pak, AbbVie), which comprised 47% of the drugs, according to the results. The lowest rate of DDI’s were reported with grazoprevir/elbasvir (Zepatier, Merck), which accounted for 11% of the drugs used. Regarding combination antiretroviral therapies, the researchers suggested that daclatasvir/sofosbuvir has no contraindications. For patients with genotype 1/4 HCV, 75% of patients taking grazoprevir/elbasvir must alter the combination antiretroviral regimen. “This study showed that co-medication use in the aging HIV/HCV population is frequent and diverse,” the researchers concluded. “There is a high potential for DDIs between DAAs and co-medication/[combination] ART.”

It is of note that the FDA recently approved sofosbuvir/velpatasvir (Epclusa, Gilead) for treatment in HIV/HCV coinfected populations.

“Approximately one-third of HIV- infected patients are coinfected with chronic HCV,” Lo Re said. “Rates of liver decompensation are higher for HIV/HCV-coinfected patients compared to those with HCV alone. However, studies have repeatedly shown that coinfected patients are no different than HCV monoinfected patients with regards to cure of chronic HCV with DAAs. However, it is important to consider antiretroviral-DAA interactions, and these studies and approvals are important in that regard.”

For Sajadi and Stafford, it comes down to vigilance on the part of clinicians, keeping these patients in the system and getting them the comprehensive care that they need, whatever form that may take. “We think this points to an added benefit of treating chronic HCV as soon as possible,” they wrote. – by Rob Volansky

• References:
• Campbell CA, et al. MMWR. 2017;66:465–469
• Hoorenborg E, et al. AIDS. 2017;doi:10.1097/QAD.0000000000001522.
• Horyniak D, et al. Int J Drug Policy. 2017;doi:10.1016/j.drugpo.2017.06.006.
• Lo Re V, et al. Pharmacoepidemiol Drug Saf. 2017;doi:10.1002/pds.4258.
• Smolders EJ, et al. J Acquir Immune Defic Syndr. 2017;doi:10.1097/QAI.0000000000001488.
• Stafford KA, et al. Medicine (Baltimore). 2017;doi:10.1097/MD.0000000000007348.
• Vanhommerig JW, et al. AIDS. 2017;doi:10.1097/QAD.0000000000001592.

• For more information:
• John T. Brooks, MD, can be reached at 1600 Clifton Road Atlanta, GA 30329-4027; email: moy9@cdc.gov.
• Vincent Lo Re III, MD, MSCE, can be reached at 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104; email: vincentl@mail.med.upenn.edu.
• Mohammad Sajadi, MD, can be reached at 725 W. Lombard St. (N548), Baltimore, MD 21201; email: KStafford@ihv.umaryland.edu.
• Kristen A. Stafford, MPH, PhD, can be reached at 725 W. Lombard Street, Room S522, Baltimore, MD 21201; email: msajadi@ihv.umaryland.edu.
• Lianping Ti, PhD, can be reached at BC Centre for Excellence in HIV/AIDS, St. Paul’s Hospital, 608–1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6; email: Rena.Heer@edelman.com.

Disclosures: Lo Re reports receiving research funding for the University of Pennsylvania from AstraZeneca for evaluating oral antidiabetic drugs. Brooks, Sajadi, Stafford, and Ti report no relevant financial disclosures.