January 16, 2015
12 min read

A Level Playing Field: HIV/HCV Coinfection in the DAA Era

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The shifting landscape of hepatitis C virus management has forced the clinical community to continuously re-evaluate treatment paradigms for many patient populations, including those coinfected with HIV. Although the news is mostly good — a number of novel direct-acting antiviral agents and combinations have yielded sustained virological response rates around 90% in cohorts with HIV/HCV — a host of challenges remain.

In short, dealing with coinfected populations is not as easy as writing a prescription for sofosbuvir (Sovaldi, Gilead Sciences) or ledipasvir/sofosbuvir (Harvoni, Gilead Sciences), according to Curtis Cooper, MD, associate professor of medicine in the division of infectious diseases and director of The Ottawa Hospital and Regional Viral Hepatitis Program University of Ottawa. “Prescribing the medications is the easy part of managing coinfected patients,” he said. “So many people with HIV and HCV have concurrent medical issues and have been marginalized in so many ways. They are dealing with mental health issues, substance abuse issues, housing and poverty issues. As clinicians, these are problems we can’t ignore.”

Curtis Cooper

Curtis Cooper

Many of these obstacles keep patients out of the clinic. “Keep in mind, with [direct-acting antivirals], adherence is critically important,” Cooper said. “Without addressing these factors, many people living with HIV will continue to have suboptimal HCV treatment outcomes.”

HCV Next spoke to a cross section of experts about managing coinfected populations. Topics related to DAAs included cost, treatment duration and drug-drug interactions with antiretroviral therapies. Experts also weighed in on HIV/HCV in men who have sex with men (MSM) and injection drug users and how these issues present barriers to care.

“Even though these challenges are often difficult to address, we have to remember to look at the whole patient,” Cooper said. “There are well established multidisciplinary models of care for how this group can be optimally treated.”


As results with DAA therapies suggest parity between co-infected and monoinfected populations, understanding the current landscape is a critical component to continuing to achieve those comparable outcomes in patients with HIV.

At The Liver Meeting 2014, Mark S. Sulkowski, MD, of Johns Hopkins University, presented findings from the randomized, open-label TURQUOISE-I study, which evaluated the AbbVie 3D combination (ritonavir-boosted paritaprevir with ombitasvir and dasabuvir) plus ribavirin regimen for 12 or 24 weeks in 63 patients. Study eligibility included previously untreated patients or those who underwent prior therapy with pegylated interferon and ribavirin. Cirrhotic and noncirrhotic patients were included, along with a CD4 count of at least 200 cells/mm3 or CD4 percentage of at least 14%, and plasma HIV-1 RNA suppressed on a stable regimen containing atazanavir or raltegravir (Isentress, Merck).

Patients in the 12-week arm demonstrated an end-of-treatment response rate of 96.8% and a 4-week SVR rate of 93.5%. In the 24-week group, the end-of-treatment rate was 96.7%. The regimen was well tolerated, with no serious adverse events or discontinuations due to adverse events reported.

“The high virologic response rate and low rate of treatment discontinuation observed with 3D [plus ribavirin] in treatment-naive and treatment-experienced [genotype] 1 HCV/HIV-1 coinfected patients with or without cirrhosis is consistent with those in HCV [genotype] 1-monoinfected populations receiving this regimen,” the researchers concluded in the abstract.

The PHOTON Studies

The PHOTON-1 and PHOTON-2 studies also are key phase 3 data sets for coinfected populations. Sofosbuvir 400 mg was administered once daily along with ribavirin 1,000 mg to 1,200 mg per day for 12 or 24 weeks. The lowest 12-week SVR rate was reported in treatment-naive patients with genotype 3 disease who were treated for 12 weeks (67%). SVR12 rates for all other treatment groups — including treatment-naive and treatment-experienced patients with genotypes 1 to 4 disease treated for 12 or 24 weeks — ranged from 80% to 91%.


Laurent Cotte, MD, of Service des Maladies Infectieuses et Tropicales at the Croix-Rousse Hospital, put the findings in perspective. “The SVR12 was far better in the pretreated genotype 3 patients than in naive patients, demonstrating that a 12 weeks treatment was insufficient for this genotype,” he said.

Laurent Cotte

Laurent Cotte

David Wyles, MD, associate professor of medicine in the division of infectious diseases at the University of California at San Diego, echoed this response. “Since the PHOTON 1 study only used 12 weeks in treatment-naive patients with genotype 3 resulting in a lower response, it lends further support to the 24-week recommended duration for that population,” he said, adding that he would not routinely recommend 24 weeks of therapy for treatment-experienced patients with HCV genotype 2.

Other Findings

The C-WORTHY study included 59 noncirrhotic patients with HIV and HCV genotype 1 disease who were treated with MK-5172 (a protease inhibitor; Merck) and MK-8742 (an NS5A inhibitor; Merck) with or without ribavirin for 12 weeks. Results indicated an SVR4 rate of 100% for patients in the ribavirin group and 90% without ribavirin.

The ERADICATE study included 50 coinfected patients with HCV genotype 1 who were treated with ledipasvir/sofosbuvir. The SVR12 rate was 100% among 37 patients being treated with ART.

“History will show 2014 as the beginning of the interferon-free era, both in HCV-monoinfected patients and in HIV/HCV-coinfected patients,” Cotte said. “The results presented so far demonstrate that HCV infection in HIV-coinfected patients can be cured with the novel DAAs with similar results seen in HCV-monoinfected patients. However, these results are observed in HIV-infected patients receiving successful ART, with normal or near-normal CD4 counts and an undetectable HIV viral load, or in the minority of patients with persistent-normal CD4 counts in the absence of ART.”

Cotte said the clinical community is still investigating the effect of DAAs in patients who never regain normal CD4 counts. This issue may grow in importance as researchers investigate how DAAs and ART work together.

Fred Poordad, MD, of the Texas Liver Institute and University of Texas Health Science Center in San Antonio, summed up the implications of this research. “What all of these studies tell us is that the days of this population having suboptimal responses are over,” he said. “The good news: This is no longer a difficult-to-cure population.”

Drug-drug Interactions

Poordad put the discussion of drug-drug interactions into simple terms. “We are not yet in a ‘no brainer’ era,” he said. “Some thought and diligence to assess for drug interactions is needed regardless of which HCV regimen is being used.”

Most of the data indicate that drug-drug interactions are minimal with sofosbuvir, Cooper said. However, he voiced some concerns with simeprevir (Olysio, Janssen), daclatasvir (Bristol-Myers Squibb) and ledipasvir (Gilead). “They all use similar enzymes for their metabolism,” he said.

“Simeprevir has strong interactions with cytochrome p450 inhibitors and cannot be combined with any HIV protease inhibitors, excluding, de facto, 42% of patients,” Cotte said. “Daclatasvir has been studied in combination with all major families of drugs, including nucleoside inhibitors, protease inhibitors, non-nucleoside inhibitors and integrase inhibitors, allowing combinations with a wide area of ART.”

The AbbVie regimen also resulted in hyperbilirubinemia in patients receiving atazanavir, according to Wyles. “This was not a toxicity issue but a cosmetic one,” he said. “It is a known combination of interactions of the various meds on bilirubin processing and transport. It does not result in increased toxicity.”

Direct comparison of DAAs with a focus on adverse events should be undertaken, according to Cotte. “Since the development of these drugs was clearly accelerated, and given the small numbers of patients treated with some of these combinations, one should be extremely cautious in the future regarding the potential emergence of previously unreported toxicities when larger number of patients will be treated,” he said. “For example, the renal toxicity observed with telaprevir (Incivek, Vertex Pharmaceuticals) was unreported in phase 2 and 3 studies.”


Safely Using ART

Ellen M. Tedaldi, MD, professor of medicine and director of the Comprehensive HIV Program at the Temple University School of Medicine, said the 3D combination is safe with tenofovir (Viread, Gilead Sciences), raltegravir and atazanavir. “However, the use of ritonavir in the 3D regimen and other forthcoming combinations may introduce some side effect and interaction issues,” she said.

Cotte said the current body of research only includes studies with selected ART therapies, with HIV protease inhibitors largely excluded. “Since most of HIV/HCV-coinfected patients in industrialized countries may have a long history of antiretroviral treatment — they may have received suboptimal ART in the past, and may have HIV with known resistance to one or more antiretrovirals — not all of them could be treated with ART with minimal potential for drug-drug interactions such as raltegravir-nucleoside inhibitors or rilpivirine- (Edurant, Janssen) nucleoside inhibitor combinations,” he said. “In fact, in the HepaDatAIDS French cohort of nearly 2,000 HIV/HCV-coinfected patients with detectable HCV RNA, 43% of the patients were receiving a boosted HIV protease inhibitor, and most of them would probably not be able to receive an antiretroviral combination with no effect on cytochrome p450.”

There is some theoretical concern with possible enhanced nephrotoxicity due to increased tenofovir exposure when it is given in combination with certain DAAs, according to Wyles. “There is no data at this time to indicate this actually happens, but it is alluded to pretty strongly in the Harvoni package insert,” he said.

For Cotte, the problem is not simply combining the two types of drugs to avoid interactions. “We must define a specific regimen of DAA and ART that will give acceptable concentrations of both DAAs and ART, without underexposure, which could favor virological failure, or overexposure, which could be associated with an increased toxicity,” he said.

The problem, then, is not having interactions, but dealing with the interactions that arise, according to Cooper. “The drug-drug interactions don’t represent showstoppers for our patients,” he said. “We just need to be aware of them and take appropriate cautionary steps, which sometimes means altering ART regimens. In almost all cases, these patients can be treated safely and successfully.”

Other Comorbidities

Tedaldi’s institution recently began reviewing the status of HIV/HCV population with the HIV Outpatient Study. Temple University School of Medicine is part of an observational database with the CDC that includes nine centers. “We looked at the readiness of this population and found potential challenges when considering the DAAs,” she said. “Some of these included lack of screening and basic monitoring for HCV infection, low rates of protective vaccination against other viral hepatitides, as well as inadequate control of HIV infection itself. The basic adherence to guidelines even in this emerging era of new therapies is still a challenge.”

Tedaldi said obesity, diabetes and other comparably significant comorbidities in patients with HIV could impact the success of DAA therapies. “These are patients at risk for liver failure from steatohepatitis or nonalcoholic steatohepatitis,” she said. “There are still patients struggling with drug and alcohol abuse who remain at risk for reinfection with HCV or may not have the same SVR rates if they are using other hepatotoxic substances.”

Cotte built on this point. “One should expect the need to combine DAAs with other families of drugs with potential interactions, such as cholesterol-lowering agents and treatment for hypertension,” he said. “A statin treatment can usually be suspended for the 12 to 24 weeks of a DAA treatment, but the choice may not be as simple for other drugs. It may take a multidisciplinary team to handle these issues.”


Shortening Treatment Duration

Although much research is being conducted to determine whether 8 or 6 or even 4 weeks of therapy can be effective in monoinfected and coinfected populations, 12 weeks of mostly tolerable treatment is a vast improvement over 48 weeks of toxic interferon, according to Cotte. “With better tolerated drugs, the need for a shorter duration is not as important, given where we came from,” he said. “Three months of treatment is still very attractive. We’ll see what the future holds.”

“In general, I think these are going to settle in right around where they are for monoinfection, at 12 weeks for most,” Wyles said, adding that further data are needed for 8 weeks of therapy. “I would not routinely go to 8 weeks in coinfected patients with Harvoni until we have some data.”

As for prolonged treatment, Wyles said he predicts that the subset of patients — namely, cirrhotics and especially treatment-experienced — will likely require 24 weeks of treatment, similar to the monoinfected patients who need 24 weeks.

Cost Consideration

Most experts said they believe that more drugs on the market will drive current drug prices down, possibly within the next few years. Clinicians may be able to hold off on treating many patient groups, including non-cirrhotics with minimal fibrosis, until this happens. But millions of patients require immediate intervention, and many of those are coinfected with HIV.

The issue, though, is not just one that confounds the clinical community at the patient level. “The price of DAAs is currently a real problem at the national level, since no country in the world can afford the cost of treating every HCV-infected patient at the same time,” Cotte said.

“Some payers were not allowing HIV physicians to prescribe the newer DAAs,” Wyles added. “This will be an issue to watch going forward.”

David Wyles

David Wyles

Cost also ties into duration of therapy, according to Wyles. Some patients are treated for 16 or 24 weeks with diminished efficacy, depending on the genotype and regimen. “We are seeing significantly increased costs with twice the duration,” he said.

Then there is the controversial issue of reinfection. Put simply, patients who acquire HCV again after they have been cured will require re-treatment, which essentially doubles the cost burden on the health care system. But Cooper said he believes that this may be an over-stated issue in HIV/HCV-coinfected populations. “We see very few coinfected patients who return with re-infection after successfully eliminating the infection,” he said. “This is an issue that we should pay attention to because this is often used as an excuse for not funding these programs. In reality, this should be a relatively small issue. Once treated and cured, most will not return with a new infection.”

Lifestyle Factors

Wyles said the debate about increasing reinfection rates has arisen because of an uptick in high-risk sexual behaviors, particularly among some MSM. There is an argument in the clinical community that unsafe sex “is back.”

“I’m not sure it ever completely went away,” Cooper said. “At the clinic level, we have frank discussions about risk. We talk to our patients about how they may put themselves and others at risk when they have unprotected sex. At the public health level, campaigns are important to get the word out that unprotected sex can still result in negative and life-long consequences.”

For Cooper, it is imperative that clinicians treat the whole patient, not just the disease. “If you have a patient actively injecting drugs or abusing alcohol, we have to get them engaged in harm reduction programs,” he said. “We also have to find ways to keep impoverished or homeless patients engaged in the system.”


Tedaldi agreed. “For some patients, we need to focus simply on controlling their HIV disease first,” she said. “There are still many patients who are not adequately suppressed on their HIV therapies. That could impact the success of these new HCV therapies and adherence even in the short run.”

Looking Ahead

Data from Garg and colleagues presented at IDWeek 2014 indicated that HCV screening in patients with HIV is not as prevalent as previously thought, according to Wyles. “Their data suggested that only about 80% had been screened,” he said. “Provider and patient knowledge about screening protocols are going to be major issues going forward because this will impact access and treatment.”

Given the cost of drugs and the necessity of carefully choosing who to treat, increased screening has led to a discussion about who to treat first. “Prioritizing is not a bad thing,” Poordad said. “Treat those that need it most first, and then address the others. The patients with advanced fibrosis and extrahepatic disease are first on most clinicians’ lists. Since the coinfected patients tend to have more advanced fibrosis at an earlier time point in their disease, they will be high priority.”

Continued vigilance of cirrhosis and fibrosis remains critical, according to Tedaldi. “This is a rapidly changing landscape,” she said. “But we definitely need to continue to initiate therapy in patients with early cirrhosis based on biopsy or higher fibrosis scores.”

Poordad underscored this point. “The challenge in treating the connected patient is not curing them,” he said. “It is understanding that the progress to cirrhosis is faster than what we see in monoinfected patients. Clinicians must be diligent to not miss cirrhosis in this population. Patients develop advanced disease at a young age in many cases.”

Fred Poordad

Fred Poordad

Tedaldi said she believes that the algorithm for selecting candidates for DAA therapy will require ongoing refinement, but that the news, in general, is positive. “The enthusiasm for the new treatments will also create a renewed interest in hepatic health, in general,” she said.

“There is no doubt that DAA therapy represents a quantum leap forward,” Cooper added.

For Wyles, the issue comes down to coinfected and monoinfected patients reaching a level playing field. “In a few years, many of the considerations, such as treatment regimens and responses, making patients with HIV co-infection a special population will go away,” he said, though faster progression will maintain some prioritization for co-infected patients.

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Rockstroh JK. Abstract #195. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston.
Sulkowski MS. Abstract #236. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston.
Sulkowski MS. JAMA. 2014;312:353-361.
Sulkowski MS. MOAB0104LB. Presented at: 20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia.
Townsend KS. Abstract #86. Presented at: The Liver Meeting; Nov. 7-11, 2014; Boston.
For more information:
Curtis Cooper, MD, can be reached at the Department of Medicine, The Ottawa Hospital, General Campus, 501 Smyth Road, Box 206, Ottawa, ON K1H 8L6; email: ccooper@toh.on.ca.
Laurent Cotte, MD, can be reached at Hôpital de la Croix-Rousse, 103 Grande-Rue de la Croix-Rousse, 69004 Lyon, France; email: laurent.cotte@chu-lyon.fr.
Fred Poordad, MD, can be reached at The Texas Liver Institute-University of Texas Health Science Center, 607 Camden St., Suite 101, San Antonio, TX 78215; email: poordad@uthscsa.edu.
Ellen M. Tedaldi, MD, can be reached at 1316 W. Ontario St., Philadelphia, PA 19140; email:  Ellen.Tedaldi@tuhs.temple.edu.
David Wyles, MD, can be reached at Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, SCRB #404, La Jolla, CA 92093-0711; email: dwyles@ucsd.edu.
Disclosures: Cooper reports associations with AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Roche and Vertex. Cotte reports associations with Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme-Chibret, Mylan and ViiV Healthcare. Poordad reports associations with a number of device and pharmaceutical companies, including AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals and ZymoGenetics. Tedaldi reports associations with Gilead Sciences and Merck. Wyles reports associations with AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck and Tacere.