HIV makes HCV infection worse. Compared with people infected only with HCV, those burdened by both viruses get cirrhosis faster1,2 and die sooner.3,4 Taking combination antiretroviral therapy (cART) eased HIV's baneful impact on HCV progression in a 3567-person meta-analysis, but not completely.1

Does HCV infection make HIV infection worse? Studies addressing this question yield different -- and sometimes conflicting -- answers. No one should be surprised. These studies used different methods to analyze different populations, different endpoints, and different periods (before and after the arrival of cART). And some of the cART-era studies involve more toxic and inconvenient antiretrovirals rarely used today. According to an AIDS Clinical Trials Group (ACTG) team that recently explored these issues,5 the controversy breaks down this way:

  • Natural history studies show that -- before HCV/HIV-coinfected people start cART -- their HIV disease progression largely tracks with that of people infected only with HIV.6-8
  • After people begin cART, some studies found that HCV/HIV-coinfected people have smaller or delayed CD4 gains than HIV-monoinfected people.9-15
  • A few studies found, though, that CD4 differences between coinfected and monoinfected people wane as cART continues.16,17
  • And a cluster of other studies found no link between coinfection and dampened CD4 gains.18-25
  • Three studies that examined the impact of coinfection on virologic response to cART found no link.10,11,26
  • A 2009 meta-analysis13 and other studies27,28 discerned no tie between HCV/HIV coinfection and AIDS-defining endpoints.
  • But one study did link coinfection with AIDS endpoints.29

This article dissects these and other studies to answer three questions:

  1. How does HCV infection affect mortality in people with HIV?
  2. How does HCV infection affect progression to AIDS and other clinical outcomes?
  3. How does HCV infection affect response to cART?

Answers to these questions have already informed guidelines on caring for people with potential and confirmed HCV/HIV coinfection. Tables 1 and 2 outline current guidelines. A 1-page handout in this issue of RITA! offers HCV/HIV patients 10 pointers on preventing transmission of these viruses and avoiding treatment complications.

Table 1. Screening and Prevention Guidelines for HCV and HIV Coinfection

Screening

Everyone with HIV should be screened for HCV infection when entering care, preferably before starting cART (DHHS Adult),30 and annually thereafter (HIVMA/IDSA).31

People positive for HCV antibody should have HCV RNA measured to determine whether HCV infection is active (HIVMA/IDSA).31

HCV RNA should be measured in HCV antibody-negative people with a history of injection drug use or unexplained increased serum transaminases because HCV antibodies do not develop in approximately 6% of HCV/HIV-coinfected people (HIVMA/IDSA).31

Infants born to HCV- or HBV-infected women should be screened for HCV and HBV. Infants can be tested for HCV RNA after age 2 months and for HCV antibody after 18 months of age (HIVMA/IDSA).31


Prevention

To assess kidney function, HCV/HIV-coinfected people should be screened for proteinuria when they begin care and annually thereafter (HIVMA/IDSA).31

All HCV/HIV-coinfected people should be tested for hepatitis A virus (HAV) and hepatitis B virus (HBV) and vaccinated if not immune (HRSA).32

HCV/HIV-coinfected people vaccinated against HBV in the past should have their anti-HBV titer checked to make sure they remain protected (HRSA).32


Patient Counseling

People with HCV infection should be counseled to avoid alcohol and medications toxic to the liver, including fluconazole, isoniazid, and large doses of acetaminophen (HRSA).32

People with HCV infection should be counseled to reduce risk of HCV transmission through unprotected sex, perinatal exposure, or sharing drug-injecting equipment, razors, tattoo equipment, or sex toys (HRSA).32

See the patient guide in this issue of RITA!.

Table 2. HIV and HCV Care Guidelines for People With Coinfection

Combination antiretroviral therapy (cART) should be considered for coinfected patients regardless of CD4 count because cART may slow liver disease progression by preserving or restoring immune function and reducing HIV-related immune activation (DHHS Adult).30

Liver function should be monitored closely in coinfected people on cART (HRSA).32

Consideration of potential drug-drug interactions and overlapping toxicities should guide antiretroviral selection in coinfected people receiving treatment for HCV infection (DHHS Adult).30

Because of pill burden, drug-drug interactions, and overlapping toxicities when treating coinfected people, some clinicians may choose to defer cART until antiretroviral-naive people with a CD4 count at or above 500 cells/mm3 complete anti-HCV therapy* (DHHS Adult).30

For people with a CD4 count below 200 cells/mm3, it may be preferable to start cART first and begin HCV therapy after the CD4 count rises (DHHS Adult).30

Interferon alfa and pegylated interferon are not recommended during pregnancy, and ribavirin is contraindicated during pregnancy (DHHS Perinatal).33

Men and women taking ribavirin should use contraception consistently during ribavirin therapy and for 6 months after completing ribavirin therapy (HRSA).32

Treatment of HCV infection in HIV-positive people is evolving rapidly as direct-acting antivirals (DAAs) become available and their interactions with antiretrovirals are defined. For the latest treatment advice, see the table "Unique Patient Populations: HIV/HCV Coinfection" in Recommendations for Testing, Managing, and Treating Hepatitis C, from the Infectious Diseases Society of America. Also see the article on DAAs in this issue of Research Initiative, Treatment Action! and the interview with Douglas Dieterich.

People with HCV infection who inject drugs should be strongly counseled to enter a treatment program to end their dependence (HRSA).32

* Recent and ongoing approval of stronger direct-acting antivirals (DAAs) for HCV infection with 8- to 24-week courses could strengthen the rationale for treating HCV infection before starting cART.34

Impact of HCV on Mortality With HIV

The impression that HCV does not affect survival in people with HIV dates to the pre-cART era, when HIV-positive people died of AIDS long before they could die of heart, kidney, or liver disease. Two emblematic studies involve medium-size U.S. HIV cohorts -- one largely male and one entirely female.35,36

Researchers compared survival in 115 HIV-positive veterans with HCV and 235 without HCV in the HIV Atlanta Veterans Affairs Medical Cohort Study (Table 3).35 These people were in care at some point from January 1992 to May 1997, and all but 5 were men. Most participants had taken antiretrovirals, but only 20% had taken a protease inhibitor, so this was a largely cART-naive cohort. Multivariate analysis identified no links between antiretroviral treatment history and HCV antibody positivity.

Table 3. Impact of HCV Infection on Survival in Atlanta VA Cohort Before cART and With cART
 Staples35Anderson43
Observation PeriodJanuary 1992 Through May 1997January 1997 Through May 2001
 HCV plus HIV
(n = 115)
HIV only
(n = 235)
HCV plus HIV
(n = 306)
HIV only
(n = 664)
Had AIDS81 (70%)164 (70%)213 (70%)433 (65%)
Took cART19 (16%)*50 (21%)*199 (65%)509 (77%)
Died24 (21%)46 (20%)67 (22%)72 (11%)
Time from HIV Dx to deathNo difference by Cox proportional hazards modelaHR HCV+ vs HCV-: 2.47
(95% CI 1.26 to 4.82, P = 0.0085)
Time from AIDS Dx to deathNo difference by Cox proportional hazards modelaHR HCV+ vs HCV-: 1.84
(95% CI 1.09 to 3.10, P = 0.022)

aHR, adjusted hazard ratio; Dx, diagnosis.

* Reported as protease inhibitor use.

P = 0.001.

P < 0.0001.

The same proportion of people in the coinfected group and the HIV-only group -- 70% -- had AIDS.35 Twenty-four people with coinfection (21%) and 46 with HIV alone (20%) died during the study period (Table 3). Cox proportional hazards models discerned no difference between the coinfected group and the monoinfected group in time from HIV diagnosis to death or time from AIDS diagnosis to death. In this group, largely in care before the benefits of cART took hold, HCV coinfection did not shorten survival.

A Women and Infants Transmission Study (WITS) analysis involved 652 women -- 190 (29%) with HCV and none with an AIDS diagnosis -- who enrolled in the cohort when pregnant from 1989 through 1995, before cART arrived.36 Only 124 women (19%) tried a cART combination during follow-up (with no difference between coinfected and monoinfected women). Forty-three women (7%) died, 26 of them (4%) without a documented AIDS diagnosis. Cox proportional hazards analysis determined that coinfected women did not have faster progression to an initial class C AIDS diagnosis or death (relative hazard 0.75, 95% confidence interval [CI] 0.37 to 1.53).

AIDS as a King-Size Competing Risk

These two studies35,36 share a key limitation: The investigators did not report (and perhaps did not know) what caused the deaths in their cohort. Was it AIDS, liver failure, or something else? Knowing the cause of death is critical to understanding whether HCV infection shortens survival in people with HIV because of a statistical bugbear called competing risk. A person who runs a risk of more than one mutually exclusive mortal event -- such as death from AIDS and death from HCV-induced liver failure -- has competing risks.37 The risks compete because if one happens, the other can't.

From the dawn of the HIV epidemic until wide use of cART, AIDS became a competing risk as population-shredding as the black death in 1666 London or influenza in 1918 across the globe. Until the mid-1990s HIV-positive men and women died of AIDS in their 30s and 40s -- long before they could succumb to heart disease or lung cancer -- even if they had relatively high heart or cancer risks. Compared with HIV infection, HCV infection is an indolent disease. About 10 years elapse between untreated HIV infection and AIDS in the United States,38 and perhaps another 2 years between untreated AIDS and death.39,40 In contrast, people with untreated HCV infection can live without cirrhosis for 20 to 30 years and sidestep liver failure for years beyond that.41 So a person infected with both viruses runs a much higher risk of dying from AIDS than from liver disease, even if infected with HCV 5 or 10 years earlier than with HIV.

A pre-cART study from Spain shows how handily AIDS outcompetes liver disease in coinfected and inadequately treated people.42 The cohort included 328 antiretroviral-treated people seen from 1989 through 1996 -- before wide cART use. The group had a median initial CD4 count of 303 cells/mm3. Two thirds (65%) had HCV, 5% HBV, and 3% hepatitis D virus. The researchers did not know whether 36 people (11%) lived or died. Among the remaining people, 67 died. Forty-nine of those 67 (73.1%) died of AIDS, while only 3 (4.5%) died of liver failure and 15 (22.4%) of other causes. As in the two U.S. studies,35,36 mortality did not differ between people with and without hepatitis virus infection. But AIDS killed 22 times more people than hepatitis in this group receiving inadequate treatment for their viral infections.

cART Makes Liver Disease a Top Killer

What happened when HCV/HIV-coinfected people started taking three antiretrovirals at the same time? They stopped dying of AIDS as quickly, and growing proportions began living so long with HIV they started dying of other diseases -- including liver failure and liver cancer. And study after study began showing that HCV coinfection boosted chances of death in people with HIV.

For example, whereas the pre-cART analysis of the Atlanta VA Cohort found that HCV coinfection did not affect survival,35 an early cART-era analysis of the same group did.43 The later study involved 970 HIV-positive people in care from January 1997 through May 2001, 306 of whom (32%) had HCV infection (Table 3). About two thirds in each group had AIDS, and CD4 counts when cART began were similar. During follow-up in the later study 67 coinfected people and 72 monoinfected people died, a highly significant difference (21.9% versus 10.8%, P < 0.0001).43

Multivariate survival analysis determined that coinfected people had significantly shorter survival after HIV diagnosis than did monoinfected people (hazard ratio [HR] 2.47, 95% CI 1.26 to 4.82, P = 0.0085) (Table 3).43 Survival after AIDS diagnosis was also significantly shorter in the coinfected group (HR 1.84, 95% CI 1.09 to 3.10, P = 0.022). Taking cART for at least 1 month was independently associated with longer survival after HIV diagnosis (HR 0.25, 95% CI 0.16 to 0.39, P < 0.0001) and after AIDS diagnosis (HR 0.26, 95% CI 0.16 to 0.42, P < 0.0001). HCV coinfection did not affect short- or long-term CD4 recovery in this cohort.

Before long, enough HCV/HIV mortality studies got published to allow meta-analysis. In 2009 researchers analyzed 10 studies from pre-CART days and 27 from the cART era, all of them including HIV-positive people with or without HCV infection.13 The 10 precART studies (5 U.S./Canada, 4 Western Europe) involved 4413 people with HCV plus HIV and 10,213 with HIV alone. The 27 cART studies (12 U.S./Canada/Puerto Rico, 9 Western Europe) included 25,319 coinfected people and 61,697 with HIV alone. In the pre-cART era, a random effects model determined that coinfected people had a lower overall mortality risk than people infected only with HIV (risk ratio 0.68, 95% CI 0.53 to 0.87). (A single large study drove that outcome; because that study included only inhospital patients, the meta-analysis authors believe it may suffer from survival bias.13)

After cART arrived, that risk flip-flopped. Statistical analysis adjusted for cART use, proportion of IDUs, study duration, and sex determined that coinfected people had a 35% higher overall death risk than monoinfected people in the cART era (RR 1.35, 95% CI 1.11 to 1.6) (Table 4, Figure 1). And, notably, the risk of AIDS in the cART era did not differ significantly between coinfected and monoinfected people (RR 1.12, 95% CI 0.82 to 1.51). "Given the lack of an association between progression to AIDS and HCV coinfection," the authors observed, "the major contributor to mortality among coinfected subjects during the HAART era is likely to be liver disease."13

Table 4. Five Studies of HCV Mortality Impact in cART Era
Authorn, YearsPopulationSite(s)Key Outcomes*
Sulkowski (2002)20

HCV does not have impact
1995, 873 (44%) HCV+; 1995-2001; median followup 2.19 y in HCV+, 2.00 y in HCV-Prospective cohort of patients without AIDS starting cART; 85% of HCV+, 13% HIV- IDUBaltimoreIn cART-treated people with a baseline CD4 count of 50-200, HCV raised death risk (RH 1.85, 95% CI 1.11 to 3.07); in final model including cART use and HIV suppression, HCV had no impact on mortality (RH 1.01, 95% CI 0.65 to 1.56).
Rockstroh (2005)26

HCV has impact
5957, 1960 (33%) HCV+; 1994-2004; follow-up 3.75 y in HCV+, 2.7 y in HCV-Prospective study of EuroSIDA cohort; 77.5% of HCV+, 3.2% HCV- IDUEurope, IsraelHCV raised risk of any-cause death in fixed-factor model (IRR 1.41, 95% CI 1.13 to 1.76, P = 0.0024) and updated factor model (IRR 1.80, 95% CI 1.44 to 2.25, P < 0.0001), largely because of liver-related death.
Sullivan (2006)46
HCV does not have impact
10,481, 2024 (19%) HCV+; 1998-2004; follow-up 1.9 yAdult and Adolescent Spectrum of HIV Disease participants starting cART; 47% HCV+, 7.5% HCV- IDU10 U.S. citiesHCV did not raise risk of death (HR 1.1, 95% CI 0.9 to 1.2, P = 0.38).
Chen (2009)13
HCV has impact
87,016, 21,607 (25%) HCV+; 1996-2004; 8 studies 1-3 y follow-up, 10 >3 y, 5 did not report follow-upMeta-analysis of cART patients in 27 trials; 3%-64% IDU12 studies in U.S., Canada, Puerto Rico; 9 studies W EuropeHCV raised risk of death (RR 1.35, 95% CI 1.11 to 1.6).
van der Helm (2013)45
HCV has impact
8674, 1767 (20%) HCV+; Pre-1989-2007Europeans and Canadians with known date of HIV seroconversionEurope, CanadaHCV raised risk of death (HR 1.84, 95% CI 1.16 to 2.93).

HR, hazard ratio; IDU, injection drug user; IRR, incidence rate ratio; RH, relative hazard.

Figure 1. Risk of All-Cause Mortality With vs Without HCV
Figure 1. Risk of All-Cause Mortality With vs Without HCV A 37-study meta-analysis13 and a CASCADE Collaboration study45 both found a higher risk of all-cause mortality with HCV/HIV coinfection than with HIV alone in the cART era but not in the pre-cART era. (HR, hazard ratio; RR; risk ratio.)

A 5974-person Spanish HIV cohort study published after this meta-analysis found that all-cause mortality in HCV-negative people fell by half from 1997-2003 to 2004-2008 (adjusted incidence rate ratio [aIRR] 0.52, 95% CI 0.32 to 0.85).44 But among HCV-coinfected people, overall mortality rose nonsignificantly from 1997-2003 to 2004-2008 (aIRR 1.27, 95% CI 0.90 to 1.79).

A recent analysis of the largely European CASCADE collaboration included 936 coinfected people and 833 monoinfected people in the pre-cART era, and 1767 coinfected and 6907 monoinfected people in the cART era.45 All-cause pre-cART mortality within 15 years of HIV seroconversion was higher, but not significantly higher, in the monoinfected group (78% versus 58%). In the cART era, in contrast, a significantly higher proportion of coinfected people died of any cause within 15 years of HIV seroconversion (35%, 95% CI 31% to 39%, versus 11%, 95% CI 9% to 14%). After statistical adjustment for HIV risk group, age, and sex, coinfected people had an 84% higher risk of death from any cause than did monoinfected people in the cART era (adjusted hazard ratio [aHR] 1.84, 95% CI 1.16 to 2.93) (Figure 1).

AIDS-related mortality dropped sharply in both coinfected and monoinfected people in the cART era, although AIDS (and non-natural causes) remained the leading causes of death in the coinfected group, while AIDS (and natural causes) remained the leading causes in the monoinfected group.45 But unlike the meta-analysis,13 the CASCADE study determined that coinfected people had a higher risk of AIDS death than monoinfected people -- regardless of HIV transmission group -- in the cART era.45

The CASCADE team speculated that this difference from the meta-analysis could reflect "differences in follow-up duration, inability to correct for duration of HIV infection, different statistical methods, and [racial/ethnic] differences in patient population."45 Why would AIDS-related mortality be significantly greater in the coinfected group after cART's advent? The CASCADE team speculated that higher T-cell activation with HCV infection could upset immune function in coinfected people as cART quells HIV-induced immune activation in both coinfected and monoinfected people. Cirrhosis and advanced liver disease in coinfected people would further promote AIDS conditions. So although AIDS deaths dropped steeply in both coinfected and monoinfected people, the drop was less acute in the coinfected group. Finally, although liver-related mortality fell among coinfected people in the cART era compared with earlier years, coinfected people still died more from liver-specific causes than monoinfected people after cART arrived.

These two large analyses concurred on the key finding that HCV/HIV-coinfected people began running a higher risk of death from any cause than did HIV-monoinfected people once cART arrived. The CASCADE investigators proposed that "an increased risk of both HIV and/or AIDS and hepatitis or liver-related mortality among co-infected individuals in the cART era might suggest that co-infected patients should start HIV and HCV treatment sooner after diagnosis to reduce the likelihood of disease progression, even in the absence of liver fibrosis,"45 a stance reflecting current U.S. guidelines (Table 2).30

A large EuroSIDA study confirmed the higher risk of death from any cause with HCV/HIV coinfection than with HIV infection alone (Table 4).26 The study involved 5957 HIV-positive people, 1960 of them (33%) positive for HCV antibody. People began entering EuroSIDA in May 2004, when 3117 participants signed up. Another 1365 people joined in December 1995, the cusp of the cART era. A further 6747 people enrolled in four more waves through 2003. Follow-up for the HCV/HIV analysis continued until the autumn of 2004, by which time everyone in this analysis had started cART. Median follow-up measured 45 months in the HCV/HIV group and 32 months in the HIV-only group.

The EuroSIDA team used two multivariate models to calculate the impact of HCV coinfection on virologic response, CD4 gains, progression to AIDS, any death, and liver-related death: The first model considered fixed factors known at baseline, and the second model considered updated CD4 count, cART initiation, and diagnosis of a new AIDS illness.26 HCV coinfection raised the risk of any death 41% in the fixed-factor model (IRR 1.41, 95% CI 1.13 to 1.76, P = 0.0024) and 80% in the updated factor model (IRR 1.80, 95% CI 1.44 to 2.25, P < 0.0001). The investigators attributed these higher death rates to more than a 10-fold higher risk of liver-related death with HCV in either statistical model.

Two U.S. Studies Do Not Link Coinfection to Higher Death Risk

But two U.S. studies saw no link between HCV and a higher death risk in people with HIV.20,46 A 10-city U.S. study involved 10,481 U.S. adults and adolescents, 2024 of them (19%) with a positive HCV test (Table 4).46 Only 7% of the HIV-negative group and 2% of the HCV positive group were younger than 24. Two thirds of the HCV-positive group and almost three quarters of the negative group took cART (66.2% versus 71.2%, P < 0.0001) during a median followup of 1.9 years between 1998 and 2004. The HCV group included a significantly higher proportion of IDUs (47.4% versus 7.5%), as well as gay/bisexual men who injected drugs (11.8% versus 3.9%) (P < 0.0001) and people who injected drugs in the past 6 months (13.2% versus 2.0%, P < 0.0001).

During follow-up, 16% of HCV-coinfected people died, compared with 9.3% of the HCV-negative group. Statistical analysis controlling for alcoholism, alcoholic hepatitis, drug-induced hepatitis, being prescribed ART, a previous AIDS diagnosis, lower CD4 cell count, and age found that coinfection did not affect the risk of death (aHR 1.1, 95% CI 0.9 to 1.2, P = 0.38).

A study of people in care from January 1995 to January 2001 at the Johns Hopkins Hospital HIV Clinic in Baltimore found that HCV coinfection raised the risk of death in certain analyses but not in others (Table 4).20 The 1955 HIV-positive people in this study included 873 (44%) with a repeatedly reactive HCV antibody test. Median follow-up lasted 2.19 years in the HCV group and 2.0 years in the HCV-negative group. The HCV group was significantly older and included a higher proportion of African Americans (86% versus 68%, P < 0.001) and a higher proportion of IDUs (85% versus 13%, P < 0.001). People with HCV had a significantly lower baseline CD4 count (237 versus 266 cells/mm3, P = 0.02). No one had an AIDS illness before enrollment.

During follow-up 153 HCV-positive people (17.5%) and 168 HCV-negative people (15.5%) died.20 Cox proportional hazards regression analysis (adjusted for HCV status, age, sex, race, baseline CD4 count, and baseline viral load) discerned no mortality risk difference with versus without HCV (RH 1.05, 95% CI 0.85 to 1.30). Analysis limited to 1199 people who eventually took cART also found no mortality difference with versus without HCV (RH 1.22, 95% CI 0.22 to 1.61). The same proved true in 208 people with cART-controlled HIV replication, defined as having a viral load below 400 in 75% or more measurements (RH 1.49, 95% CI 0.33 to 6.68).

HCV did boost the risk of death in 429 people with a pre-cART CD4 count between 50 and 200 cells/mm3 (RH 1.51, 95% CI 1.01 to 2.27) and in those in this subgroup who received cART (RH 1.85, 95% CI 1.11 to 3.07).20 But in this 50-200 CD4 subgroup, multivariate Cox regression also adjusted for cART use and HIV suppression saw no HCV impact on death risk (RH 1.01, 95% CI 0.65 to 1.56). Notably, the Hopkins team found that 187 of all 1199 people (15.6%) taking cART died, compared with 6 of 208 (2.9%) with well-controlled HIV replication. In the final multivariate model, longer time on cART independently halved the risk of death (RH 0.47, 95% CI 0.36 to 0.63), while more clinic visits with a detectable HIV load raised the death risk 8 times (RH 7.96, 95% CI 2.00 to 31.66).

Why do the two U.S. studies20,46 find no association between HCV coinfection and death while the cARTera meta-analysis,13 the European CASCADE study,45 and the EuroSIDA study26 do? The list of differences between these analyses could run several paragraphs, starting with utterly different populations, formats, years of cART, and statistical methods, then grinding down to nitty-gritties like confounders controlled for versus not considered. The meta-analysis, CASCADE, and EuroSIDA combined included three times as many people as the Hopkins and 10-city U.S. study combined. The Hopkins study20 and the 10-city study46 each had about 2 years of follow-up for people with and without HIV. EuroSIDA had 3.75 years of follow-up in the HCV group and 2.7 in the HCV-negative group. In 27 cART-era meta-analysis study,13 8 studies had 1 to 3 years of follow-up, 10 had more than 3, and 5 did not report follow-up. CASCADE did not report follow-up years. So the studies finding that HCV coinfection shortened survival generally had longer follow-up than the studies that did not. The 10-city U.S. study controlled for alcoholism, alcoholic hepatitis, and drug-induced hepatitis, whereas CASCADE and EuroSIDA did not. This U.S. study did not control for injection drug use or recent injection drug use, both of which were significantly more prevalent in the HCV-positive group, though controlling for drug-induced hepatitis may amount to the same thing.

One could go on, but probably to little avail. If compelled to boil all these data down to a single take-home dictate, it might be, HCV coinfection may shorten survival in people with HIV, and clinicians should do what they can to improve survival chances, notably by starting cART as quickly as feasible, working with an HIV/liver consultant to plan an optimal HCV treatment program, and working with coinfected patients to limit other prime risk factors, such as drinking, smoking, and injection drug use.

SMART trial investigators added a compelling footnote to these analyses of how HCV coinfection affects mortality.47 SMART famously found that people who suspended cART based on CD4 count had a higher risk of opportunistic disease and/or death from any cause than did people who took continuous cART. Of the 5472 study participants, 930 (17%) had HCV or HBV coinfection. Coinfected people had more than a tripled risk of death due to nonopportunistic causes compared with monoinfected people (HR 3.6, 95% CI 2.3 to 5.6), while the risk of death from opportunistic disease proved comparable in coinfected and monoinfected people. Almost half of all nonopportunistic deaths in SMART involved coinfected people, even though they made up only 17% of the study group. Substance abuse and non-AIDS cancer were the two most-identified causes of nonopportunistic death in coinfected SMART participants. The SMART team concluded that "interruption of antiretroviral therapy is particularly unsafe in persons with hepatitis virus coinfection."47

Impact of HCV on HIV Clinical Outcomes

As with studies analyzing the impact of HCV/HIV coinfection on mortality, studies examining how HCV affects chances of HIV disease progression tell different stories before and after people started taking cART (Table 5). In pre-cART days, a 416-person Italian study48 and a 1649-person analysis of Canadians, Australians, Europeans, and South Africans enrolled in the CAESAR trial27 determined that HCV infection had no impact on CD4 declines or progression to AIDS. Everyone with HIV -- with or without HCV -- had an inexorably downward disease course.

But that changed when cART came along. Triple therapy usually halted HIV disease progression by bolstering immune function and putting HIV replication in check. Yet studies began showing that cART did not rescue HCV-coinfected people as consistently as patients without the hepatitis virus. With follow-up beginning soon after cART came online, a 1467-person study at a large London HIV clinic21 and a 5397-person analysis of the Italian Icona cohort29 found that HCV coinfection raised chances of CD4 tallies dwindling below 200 cells/mm3 or a new AIDS diagnosis (Table 5). A study of 343 HIV-positive people in Saskatchewan -- 79% with a drug-injecting history and 77% with HCV -- figured that HCV tripled chances that CD4s would dwindle below 200 cells/mm3 (HR 2.9, 95% CI 1.2 to 6.9).49

Table 5. Impact of HCV on HIV Disease Progression
AuthornPopulationSite(s)Year(s)Key Outcomes
Dorrucci (1995)48416, 214 (51%) HCV+AIDS-free, IDU or sexual transmission; known HIV seroconversion dateItalyPre-cART longitudinal studyHCV had no impact on progression to AIDS or CD4 decline <100.
Amin (2004)271649, 265 (16%) HCV+People adding 3TC or 3TC / loviride to single or dual nucleosidesCanada, Australia, Europe, South AfricaPre-cART 1995-1996 (52-wk FU)Median change in CD4 count and progression to new AIDS event similar with / without coinfection.
Stebbing (2005)211467, 85 (6%) HCV+Patients with >200 CD4s in care since cART availability in 1/1996Chelsea and Westminster Hospital, London1996-2005HCV raised chance of <200 CD4s or first AIDS event (aHR 1.52, 95% CI 1.07 to 2.17, P = 0.019).
d'Arminio Monforte (2009)295397, 2421 (49%) HCV+Icona cohort patients enrolled when ART-naiveItaly1997-2008HCV raised chances of AIDS diagnosis (aRR 2.61, 95% CI 1.88 to 3.61).*
Konrad (2013)49343, 264 (77%) HCV+Mainly (79%) IDU HIV+ populationTwo clinics in SaskatchewanDiagnosed 2005-2010HCV tripled risk of CD4 decline <200 (HR 2.9, 95% CI 1.2 to 6.9).
Chen (2009)1321,607, 5334 (25%) HCV+Meta-analysis of cART patients7 studies in Canada, Europe, U.S., Taiwan1996-2004In pooled analysis, HCV did not raise chance of new AIDS diagnosis (aRR 1.12, 95% CI 0.82 to 1.51).†¶
van der Helm (2013)459164, 2015 (22%) HCV+Europeans and Canadians with known date of HIV seroconversionEurope, CanadaPre-1989-2007HCV raised chances of AIDS-related mortality in cART era in IDUs (aHR 2.43), MSM (aHR 3.11), and others (aHR 3.43).

aRR, adjusted relative rate; FU, follow-up; MSM, men who have sex with men.

* AIDS-defining illnesses included bacterial infection (aRR 3.15, 95% CI 1.76 to 5.67), HIV-related disease (wasting and dementia, aRR 2.68, 95% CI 1.03 to 6.97), and mycotic disease (aRR 3.87, 95% CI, 2.28 to 6.59).

† Did not include d’Arminio Monforte29 or Konrad.49

¶ Analysis of 7 other studies defining progression as either an AIDS diagnosis or death determined that HCV coinfection raised the risk of progression almost 50% (aRR 1.49, 95% CI 1.08 to 2.05).

‡ People infected heterosexually or via blood products.

The 2009 meta-analysis of 7 HCV/HIV studies in Canada, Europe, the United States, and Taiwan during the cART era found that HCV infection barely budged chances of a new AIDS diagnosis when compared with HIV alone (aRR 1.12, 95% CI 0.82 to 1.51).13 But this meta-analysis did not include the large Italian study that found more than a doubled risk of an AIDS diagnosis with versus without HCV,29 and it did not include the small Saskatchewan study that linked HCV coinfection to a CD4 drop below 200 cells/mm3 or a new AIDS diagnosis.49 Adding those 5740 patients to the meta-analysis would have boosted the risk of HIV disease progression with HCV, perhaps into significant terrain. The meta-analysis did find that coinfection inflated chances of an AIDS diagnosis or death about 50% (aRR 1.49, 95% CI 1.08 to 2.05).

The 2013 CASCADE cohort analysis did not consider a new AIDS diagnosis or waning CD4 counts as an endpoint.45 But HCV coinfection more than doubled or tripled chances of AIDS-related mortality in the cART era, depending on HIV transmission group (Table 5).

Together these studies (Table 5) offer compelling evidence that -- as cART began to rescue people from AIDS -- it left behind many coinfected with HCV. With these findings in mind, the CASCADE team stressed "the importance of early diagnosis of HCV infection in HIV-infected individuals and the need for routine screening of HCV among high-risk groups, including those not (yet) infected with HIV."45 They proposed that their results "highlight the importance of interventions to increase the uptake of HCV treatment in co-infected individuals." Findings in multiple populations that HCV raises chances of AIDS or a falling CD4 count lend credence to data indicating that HCV boosts mortality in people with HIV, the issue examined in the preceding section.

HCV Coinfection and Non-AIDS Disease Risk

HCV has a profound impact on mortality in people with HIV not only because it leaves many vulnerable to AIDS (preceding section), but also because it has far-flung repercussions on risk and progression of deadly non-AIDS diseases. Research indicates that HCV affects kidneys, heart, bones, brain, and eyes -- all highly pregnable organs in people with HIV infection (Figure 2).

Figure 2. Non-AIDS Impact of HCV With HIV
Figure 2. Non-AIDS Impact of HCV With HIV Studies link HCV coinfection in HIV-positive people with (from top center clockwise) chronic kidney disease, cardiovascular disease and acute myocardial infarction, fractures, neurocognitive impairment, and neuroretinal syndrome. (Illustrations from Servier Medical Art.)

HCV coinfection did not heighten renal or cardiovascular disease prevalence in a 1996-2001 age-adjusted analysis of 823 HIV-positive people in the HIV Outpatient Study.50 But more recent and larger analyses did find ties between HCV and damaged kidneys or heart. Analysis of 3441 cART-treated people enrolled in the SMART and ESPRIT trials included 473 (14%) positive for HCV antibody and 363 (10.5%) with detectable HCV RNA.51 After adjustment for renal risk factors, statistical analysis determined that HCV coinfection bolstered odds of progressive chronic kidney disease (CKD) almost 75% (adjusted odds ratio [aOR] 1.72, 95% CI 1.07 to 2.76). People with low or undetectable HCV RNA had a CKD progression risk similar to that of HCV-negative people, but those with an HCV load above 800,000 IU/mL had tripled odds of progression (aOR 3.07, 95% CI 1.60 to 5.90).

An 8235-person EuroSIDA group included 2025 (25%) positive for HCV and 983 (12%) with detectable HCV RNA.52 During follow-up starting in January 2004, CKD developed in 495 people (6%) for an incidence of 13.7 per 1000 person-years. After statistical adjustment for kidney risk factors, HCV positivity nearly doubled the risk of incident CKD (IRR 1.85, 95% CI 1.49 to 2.30, P < 0.0001). People who cleared their HCV had a CKD risk similar to that of HCV-negative people (IRR 1.17, 95% CI 0.65 to 2.09, P = 0.60). But people with HCV RNA between 615 and 500,000 IU/mL had almost a twice higher CKD incidence (IRR 1.88, 95% CI 1.31 to 2.71, P = 0.0006), and people with an HCV load above 500,000 IU/mL had more than a doubled risk of progression to CKD (IRR 2.10, 95% CI 1.54 to 2.87, P < 0.0001). Results of both studies51,52 endorse calls for early HCV therapy in coinfected people.

HCV coinfection swelled risk of cardiovascular disease and acute myocardial infarction (MI) in a study of 19,424 U.S. veterans, 32% of whom had HCV coinfection.53 As in previous research, this study recorded lower cholesterol levels in people with HCV, but HCV-positive veterans had significantly higher rates of hypertension, type 2 diabetes, and smoking. Through more than 76,000 person-years of follow-up in the cART era (1996-2004), cardiovascular disease and acute MI incidence were significantly higher in HCV-coinfected veterans. After statistical adjustment for diabetes, hypertension, age, and cART duration, HCV inflated acute MI risk 25%, though that association stopped short of statistical significance (aHR 1.25, 95% CI 0.98 to 1.61, P = 0.072). HCV boosted cardiovascular disease risk 20%, and that association was significant (aHR 1.20, 95% CI 1.04 to 1.38, P = 0.013).

The French prospective APROCO-COPILOTE cohort involved 1281 people who began cART in 1997-1999, 26 of whom had 27 fractures during a median follow-up of 7.1 years between March 1997 and August 2007.54 Body mass index did not differ between those with and without a fracture, but people who broke a bone were more often heavy drinkers (44% versus 19.5%), more likely to have HCV coinfection (48% versus 24.5%), and had a lower baseline CD4 count (194 versus 277 cells/mm3). Multivariate analysis determined that heavy drinkers had almost tripled odds of fracture (aOR 2.9, 95% CI 1.3 to 6.5). Fracture risk was even higher in people coinfected with HCV (aOR 3.6, 95% CI 1.6 to 8.1).

Both HCV and HIV penetrate the central nervous system, so there's no surprise that studies link HCV coinfection to neurologic problems, including neurocognitive impairment and neuroretinal disorder. A small study at the University of North Carolina, Chapel Hill documented worse visual memory and fine-motor functioning in 20 HCV/HIV-coinfected people than in 45 infected only with HIV before they started cART.55 The groups had comparable HIV progression before treatment started, and no one had a history of neurologic conditions. Six months after cART began, follow-up neuropsychological testing in 13 coinfected and 31 monoinfected people indicated that coinfected people no longer had worse neurocognitive function than the monoinfected group.

A 1998-2010 study at two HIV clinics in Alberta, Canada involved 456 HIV-positive people without a substance abuse history, 91 of them (20%) positive for HCV.56 The coinfected group had a higher prevalence of multiple neurologic disorders (60.4% versus 46.6%, P < 0.05) and a higher seizure frequency (28.6% versus 17.8%, P < 0.05). Seizure risk was independent of immune status in the coinfected group but not the monoinfected group. Symptomatic HIV-associated neurocognitive disorder (HAND) was more severe in coinfected than monoinfected people. Reflecting most studies reviewed in the mortality analysis above, a significantly higher proportion of people with than without HCV in the Alberta analysis died during the study period (24.2% versus 14.5%, P < 0.05). The coinfected group had a 2.4 times higher death risk after adjustment for demographic and clinical variables.

A 2013 study by researchers at New York's Mount Sinai Medical Center and Baltimore's Johns Hopkins University focused on 1576 HIV-positive people with no record of ocular opportunistic infection.57 The group included 290 people (18%) with chronic HCV infection, 74 (5%) with cleared HCV infection, and 1212 (77%) with no HCV markers. The investigators counted 244 prevalent cases of HIV-associated neuroretinal disorder (15.5%) -- visual impairment marked by reduced contrast sensitivity and reading ability. During a median follow-up of 4.9 years, neuroretinal disorder developed in another 263 people (17%). Statistical analysis adjusted for demographics, HIV treatment, liver function, and immune status determined that people with chronic HCV infection had 54% higher odds of prevalent neuroretinal disorder (95% CI 1.03 to 2.31) and 62% higher odds of incident neuroretinal disorder (95% CI 1.13 to 2.34) when compared with HCV-negative people.

Impact of HCV on Response to cART

Among 10 large studies analyzing antiretroviral response in people starting cART, five (including an 8-cohort meta-analysis14) found that HCV coinfection impaired CD4 or virologic response to cART, four did not, and one found an early impact on CD4 gain that disappeared over 4 years17 (Table 6). No easy explanation of this disagreement screams for attention.

Table 6. Impact of HCV Coinfection on Response to cART
AuthornPopulationSite(s)Year(s)Key Outcomes*
Sulkowski (2002)20
HCV does not have impact
1995, 873 (44%) HCV+Prospective cohort of patients without AIDS starting cART; 85% of HCV+ IDUBaltimore1995-2001, median follow-up 2.19 y with HCV, 2.00 y without HCVHCV had no impact on CD4-cell or CD4-percent gains with cART.
De Luca (2002)10
HCV has impact
1320, 600 (45%) HCV+Prospective study in Icona cohort patients starting cART, 39% IDUItalyMedian 37 mo follow-up in 1997-2001HCV+ had shorter time to AIDS or death (aHR 1.55, 95% CI 1.00 to 2.41); mean CD4 gain 30 cells/mm3 less with HCV; no HCV impact on virologic response.
Kaufmann (2003)17
HCV has transient impact
985 on continous cART, 300 (30.5%) HCV+Prospective Swiss HIV Cohort Study patients starting cART, 23% IDUSwitzerlandBegan cART 1996-1997, 4 years follow-upHCV+ had lower CD4 gain in first year of cART (126 vs 151 cells/mm3, P = 0.004) but not after 4 years of cART.
Anderson (2004)43
HCV does not have impact
970, 306 (32%) HCV+Atlanta VA Cohort Study patients starting cART, 22% IDUAtlanta area1997-2001HCV did not affect CD4 gain in first 6 months of cART; IDU associated with lower CD4 gain.
Miller (2005)14
HCV has impact
6216, 2179 (35%) HCV+Meta-analysis of patients starting cART in 8 cohorts, 3% to 88% IDUAustralia, Canada, France, Italy, Spain, Switzerland, U.S.1995-early 2000sHCV+ had mean 33.4 cells/mm3 lower gain through 48 weeks of cART.
Rockstroh (2005)26
HCV does not have impact
5957, 1960 (33%) HCV+Prospective study of EuroSIDA cohort, 77.5% of HCV+ IDUEurope, Israel1994-2004HCV had no impact on virologic or CD4 response (measured as 50% or 50-cell increase).
Sullivan (2006)46
HCV does not have impact
10,481, 2024 (19%) HCV+Adult and Adolescent Spectrum of HIV Disease participants starting cART, 47% HCV+ IDU10 U.S. cities1998-2004, median 1.9 y follow-upHCV did not affect CD4 gains or virologic response in first 12 months of cART.
Potter (2010)6
HCV has impact
271 HCV+, 236 (87%) with detectable HCV RNA, 35 with cleared HCV RNACanadian Co-infection Cohort Study participants starting cART, 76% HCV RNA+ and 71% HCV RNA- IDU16 centers in Canada2003-2009Yearly CD4 gain 4 cells/mm3 in HCV RNA+ vs 26 cells/mm3 in HCV RNA- (P < 0.001).
Motta (2012)16
HCV has impact
3262, 863 (26%) HCV+Italian MASTER cohort starting cART in 2000-20089 centers in ItalyMean 4.3 y follow-upHCV lowers odds of reaching <500 HIV RNA in 1st 8 mo (OR 0.612, P = 0.01 with PIs, OR 0.717, P = 0.006 with NNRTIs); HCV lowers odds of gaining 100 CD4s in 8 months (OR 0.662, P = 0.003 with PIs, OR 0.595, P < 0.001 with NNRTIs); HCV lowers 24-mo absolute CD4 gain.
Hua (2013)5
HCV has impact
3041, 279 (9%) HCV+Participants in 4 ACTG cART trials; 52% HCV+ IDUACTG sites in U.S.NR,~early to late 2000sThrough median 132 wk follow-up, HCV linked to earlier virologic failure (HR 1.43, 95% CI 1.07 to 1.91), smaller mean CD4 increase (-33.8 cells/mm3, 95% CI -52.2 to -15.4) , earlier grade 3/4 safety event (HR 1.51, 95% CI 1.26 to 1.81), increased progression to AIDS or death (HR 2.10, 95% CI 1.31 to 3.37).

* All analyses adjusted for potential confounders.

† CD4 response analysis included only virologic responders.

ACTG, AIDS Clinical Trials Group; IDU, injection drug user; NR, not reported.

One of the no-impact studies, an analysis of 970 U.S. veterans in a prospective cohort,43 included a relatively low proportion of IDUs and assessed CD4 changes after only 6 months of treatment. But the other three no-impact studies, a Johns Hopkins cohort study,20 a EuroSIDA study26 and a 10-city U.S. analysis,46 had higher proportions of IDUs and longer follow-up. All told, the no-impact studies assessed 19,403 people, including 5163 (27%) positive for HCV. The five studies finding that HCV worsens response to cART tallied 14,110 participants, 4192 (30%) with HCV. Almost all cohort members in every study lived in Western Europe or the United States.

The 2005 meta-analysis focused on 8 cohorts of people starting cART from 1995 through the early 2000s.14 After 48 weeks of treatment, people positive for HCV had a 33.4-cell lower CD4 gain than people negative for HCV. No single study had an undue influence on the results, and cART begun before or after the year 2000 did not affect the key finding. These investigators noted that their analysis is limited by an inability to determine pretreatment CD4 counts in the cohorts assessed. Also, seven of the eight studies that reported virologic response to cART saw no difference by HCV status.

The most recent analysis compared HCV-positive and negative people enrolled in four AIDS Clinical Trials Group (ACTG) trials of first-line cART.5 All trials assessed contemporary cART regimens including efavirenz, atazanavir/ritonavir, or lopinavir/ritonavir. After substantial follow-up (median 132 weeks), HCV-positive people had worse virologic, CD4 count, and CD4 percent responses in adjusted analyses. They also ran a 50% higher risk of grade 3 or 4 safety events and a doubled risk of AIDS or death. Antiretroviral adherence was good in both the HCV-positive and negative groups. Strengths of this analysis, the researchers observed, include "randomization, rigorous study monitoring, and extensive and similar data collection." And the worse CD4 response with HCV held true when the investigators limited the analysis to people without virologic failure. The ACTG team noted that their study (like the meta-analysis14) suffers from dependence on HCV antibody testing rather than HCV RNA assessment and the relatively small proportion of HCV-positive people.

This ACTG analysis checked cART responses through 2.5 years of therapy.5 The (earlier and smaller) Swiss HIV Cohort Study (SHCS) reckoned cART responses through 4 years of treatment and determined that HCV positivity did not imperil CD4 gains over that span.17 The SHCS analysis did find worse 1-year CD4 gains in coinfected people (Table 6), but that deficit disappeared with continued cART.

The Canadian Co-infection Cohort Study was the only study that distinguished between HCV RNA-positive people with chronic HCV infection and HCV antibody-positive people with cleared infection.6 This 16-center study monitoring people from 2003 through 2009 found that those who cleared their HCV gained 26 CD4 cells/mm3 yearly, compared with a meager 4 cells/mm3 yearly in the chronically infected HCV RNA-positive group (P < 0.001). Researchers figure that 85% of HCV antibody-positive people have chronic infection.58 But the remaining 15% could have some impact on results of the 7 studies relying solely on HCV antibody testing.

If one believes the apparently preponderant evidence that HCV coinfection heightens the risk of AIDS (Table 5), believing that HCV does not affect CD4 counts or viral load requires some gymnastic reasoning.

Discussion, Reduction, Deduction

Can the harried clinician put all these HCV and HIV pieces together to decide how HCV affects HIV progression? A quick check of the reference list indicates that -- after excluding HIV care guidelines -- there are a lot of pieces: 55 if you count each study cited so far, many more if you pick out key data points from each study. One answer -- as frivolous as sounds -- is it doesn't matter which studies are right and which wrong (or less right).

A first step toward groping one's way through the research labyrinth to slay the data-spouting minotaur (Figure 3) is to ask whether an HCV impact on HIV's course makes pathophysiologic sense. It does:

  • Activated CD4 and CD8 cells (reflecting poorly controlled infection and signaling progression) reach higher levels in HCV/HIV-coinfected people than in those infected with only one or the other virus.59 T-cell activation and exhaustion in this 58-person study correlated with HCV RNA load.
  • Activated CD8 cell percentages proved higher in women positive for HIV, HCV antibody, and HCV RNA than in women positive for HIV but not HCV antibody in a 218-woman study.60
  • HCV-positive women with measurable HCV RNA had significantly higher levels of activated CD8 cells and a higher AIDS incidence than HCV-negative women, according to results of a 1307-woman analysis.61
  • HCV coinfection boosted T-lymphocyte apoptosis (cell death) in 30 HIV-positive people not taking antiretrovirals more than in 31 people infected only with HIV.62

Thus reassured, the clinician can acknowledge that a mountain of data -- reasonably interpreted -- says HCV infection makes people with HIV get sick and die faster than people without HCV. Yet there's no denying that another mountain of data says the opposite. Does it matter which mountain one decides to plant one's flag upon? The apparent answer seems to be "certainly" -- because the outcomes are sickness versus health, life versus death.

But from a different perspective -- one that offers a view of the minotaur's maze from above rather than within (Figure 3) -- debates over the clinical impact of HCV on HIV disease are academic. Would anyone suggest that failure to find an association between HCV and HIV disease progression in some studies means clinicians can relax when treating coinfected people? Or stop worrying about skyscraping HCV loads? Or delay deciding how and when to treat HCV infection?

Figure 3. Finding a Way Through the HCV/HIV Data Maze
Figure 3. Finding a Way Through the HCV/HIV Data Maze Data on how HCV affects the course of HIV infection can seem maze-like in their complexity. But sometimes the most apparently daunting maze -- seen from above like the minotaur's maze -- has a simple solution: There's only one way in and one way out. (Illustration from Wikipedia Commons)

With direct-acting antivirals (DAAs) already on hand and rapidly growing more numerous (see "DAAs for HCV/HIV Coinfection: Lots More to Learn" in this issue of RITA!), would anyone suggest delaying HCV therapy and denying a coinfected person a 90% or higher chance of cure makes sense because HCV does not, or may not, worsen the course of HIV infection? DAAs have not only transformed treatment of HCV infection; they have also radically reshaped interpretation of how HCV and HIV interact to make someone sicker or closer to death. One might delay DAA therapy to wait for an appropriate all-DAA regimen, but not because of HCV's impact on HIV.

What about conflicting data on how HCV affects antiretroviral response? If a clinician believes the five studies that saw no impact of HCV coinfection on cART response (Table 6), that clinician will have no concerns over timing treatment of HCV and HIV in the same person. If a clinician believes the four studies (including one meta-analysis) that found a diminished response to cART in people with HCV, that clinician may want to start cART first in people with advanced HIV infection (as suggested in U.S. guidelines30) and probably wants to monitor antiretroviral response more closely in people being treated for HIV and HCV at the same time.

But for both sets of providers, the imminent arrival of multiple-DAA regimens may largely render cART timing decisions moot. Delaying cART for 6 months or more in HCV-coinfected people taking pegylated interferon plus ribavirin may be an unpalatable option -- or completely out of the question -- for patients with low CD4 counts or clinical AIDS. But if DAA combinations can cure HCV infection in 6 to 12 weeks, many more HIV-positive people may be candidates for (briefly) delayed cART during HCV therapy.

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