Management of hepatitis C and B in HIV-coinfected individuals: an overview of studies presented at the 3rd IAS Conference
Mark Nelson and Laura Waters, for HIVandHepatitis.com
Although the advent of HAART has resulted in a considerable reduction in mortality and morbidity associated with HIV infection, advances in the management of hepatitis B and C both in mono- and co-infected patients continues to somewhat lag behind. This is particularly true for those coinfected with HIV and HBV or HCV, despite the high incidence of coinfection worldwide.
Liver disease remains a major cause of mortality amongst HIV-infected individuals living in developed counties with access to HAART, as well as being a significant cause of morbidity in coinfected individuals.
The 3rd International AIDS Society Conference in Rio de Janeiro included a number of presentations on coinfection, particularly HCV with new subanalyses of the APRICOT trial, and new data on the safety of antiretrovirals (ARVs) in coinfected individuals. Several epidemiological studies highlighted the high rates of concomitant HCV and HBV in HIV-infected subjects and the need for enhanced vaccination programmes in emerging HIV populations.
Unless otherwise stated, all references in this article are to the Program and abstracts of the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil.
Epidemiology of HCV
The difficulties of instituting risk reduction programmes amongst intravenous drug users (IDUs) were outlined in a poster by Aquino et al.  Low rates of HIV infection (approximately 1%) in a Philippine IDU population led to a reluctance from the local authorities to support risk management programmes. The authors used HCV testing as a marker of risky injecting practice and 80% tested positive for HCV antibody.
Hadi et al performed a prospective follow-up amongst an IDU population in Pakistan.  Levels of baseline HCV and HIV infection were 42% and 3.4% respectively amongst the 500 individuals recruited to the study and the group reported high levels of risky behaviours such as sharing of injecting equipment. During follow-up the incidence of HCV and HIV were calculated to be 22 and 1.7 cases/100 person years.
Gabelia et al analysed the risk factors for HIV and HCV infection in 2406 adults in Georgia, including over 900 IDUs.  High injecting frequency and sharing of drug using equipment were strongly associated with HCV positivity (overall rate in IDUs 58.2%), as was previous imprisonment. Rates of HIV infection in the IDU population were much lower at 0.5% and there appears to be a low rate of spread of the infection in this group. This contrasts with a longitudinal study in Vancouver suggesting increasing HIV incidence amongst IDU over the last decade. 
Armenia, until recently, had no access to ARVs. 74 HIV-positive patients were screened for eligibility for therapy (based on CD4 count and symptoms) and 29/74 were diagnosed with HCV, highlighting the high rates of HCV coinfection in many regions and the increased risk of complications secondary to disease progression and drug associated toxicity in the dual infected population. 
An Argentinean cohort analysis by Fay et al assessed the frequency of HCV antibody positivity in 250 HIV infected patients between 1997 and 2004. Forty-eight per cent were coinfected with HCV, 87.5% of whom had evidence of active disease; HCV RNA detectability was not related to risk group. Genotype 1 was the most prevalent subtype (72%), again not influenced by risk group. Fifteen per cent of HCV infected individuals were found to have a positive HCV RNA but negative antibody leading the authors to recommend HCV RNA testing as a screening test in this population. 
Finally, a prospective serological study of 312 individuals attending an out-patient unit in St Petersburg detected coinfection with HIV and either HCV or HBV in 37%; in total 27.1% tested positive for HIV-1 antibody and 26.9% of these had a positive HBV surface antigen and 80.8% a positive HCV antibody (over 75% of these individuals had a positive HCV RNA). This study reiterates the frequency of HIV/HCV coinfection in many populations. 
In contrast, a Romanian study by Benea et al found relatively low rates of HCV infection in their HIV-positive cohort (6.82%), reflecting the low levels of IDU-associated infection. 
Silva et al found that in a cohort of 2005 individuals 48% had not been screened for HCV and of those who had undergone testing, 10.9% were HCV-positive. All clinicians should test newly presenting individuals for hepatitis A, B and C, and vaccinate and retest as appropriate. 
It is well established that rates of success when treating HCV are lower in those coinfected with HIV than in moninfected individuals. Neumann et al studied HCV kinetics in an attempt to predict rates of sustained virological response (SVR) in a group coinfected with HIV and HCV (genotype 1). Twenty-three patients (11 Caucasian and 12 African-American) were treated with weekly Pegylated interferon alpha-2b (PegIntron) dosed at 1.5mcg/kg and 1200mg ribavarin once daily for 48 weeks. 
HCV RNA quantification assays were performed to monitor viral kinetics during therapy. The results revealed a rapid early phase decline in HCV RNA between day 1 and 3 followed by a transient day 3-7 rebound in 22/23 patients. The day 1-3 decline and the mean decline at day 7 were significantly greater in Caucasians.
A second phase decline occurred between week 1 and 4, again significantly faster in Caucasians; this second decline correlated with viral load at day 3 (p<0.003).
A number of factors were found not to correlate with viral kinetics including age, gender, baseline ALT and CD4 cell count. Sustained viral response (SVR) was achieved in 4/21 patients; absence of SVR could be predicted with 100% negative predictive values by a viral load > 5 log copies/mL at day 28 or day 3.
High rates of HCV RNA clearance in response to weekly Peg-IFN (Alpha-2b) 1.5mcg/kg and daily ribavirin (800-1000mg/day) were demonstrated in an open-label, prospective study amongst 17 HIV/HCV coinfected individuals in Moscow. 
In this population, 87% were IDUs and approximately 50% were HIV virologically controlled on HAART. Eleven patients (65%) achieved biochemical and virological response at 4 weeks (defined as transaminase normalisation and negative HCV RNA respectively) and 15 (88%) had negative HCV RNA levels at 12 weeks. The same number had an undetectable HCV RNA at the end of therapy, and of the nine who were followed-up to 48 weeks, all remained undetectable. Only 2 (15%) discontinued therapy prior to 24 weeks. The genotypes were not specified.
In order to assess the impact of adverse events (AEs) on rates of treatment success in HIV/HCV coinfection, Sulkowski et al analysed data from APRICOT. 
This trial compared three therapeutic strategies, pegylated interferon alfa-2a (PEGASYS) with ribavirin, peginterferon alone and standard interferon with ribavirin, all for 48 weeks duration. Safety events included treatment-related serious adverse events (AEs), premature withdrawal secondary to AEs, laboratory abnormalities (neutropenia, thrombocytopenia and anaemia) and depression; Sustained viral response (SVR) was defined as HCV RNA <50 IU/mL at the end of follow-up (week 72).
Among patients treated with peginterferon/ribavarin, treatment-related AEs and AEs leading to withdrawal of therapy were associated with the greatest reductions in SVR rates; laboratory abnormalities and depression had minimal impact on SVR in this group. These results suggest that the prevention or treatment of AEs may improve rates of SVR to HCV treatment.
Another analysis of APRICOT was presented by Lissen et al. Following the superior SVR rates achieved with peginterferon/ribavirin compared with peginterferon monotherapy and conventional interferon plus ribavirin, they analysed the histology of individuals with baseline bridging fibrosis or cirrhosis. All individuals fulfilling these histological criteria at baseline, with paired biopsy samples (15 months or less prior to randomisation and 56 or more days after treatment) were included in the analysis. Biopsies were rated using the Ishak-modified system to assess changes in histological activity index (HAI) or fibrosis score. 
Overall, peginterferon/ribavirin was shown to have the greatest impact on fibrosis and HAI scores with a mean reduction of 0.2 (SD1.5) and 2.5 (SD 2.7) respectively. The greatest improvements were achieved in cirrhotic patients, with a mean reduction in HAI of 3.3 (SD 3.5) and in fibrosis score of 0.6 (SD 1.3). Histological response (HR) was shown to be independent of SVR; HR was seen in 80% of individuals with SVR but also in 58% of those who failed to achieve SVR. The lowest HR was observed in the peginterferon monotherapy arm.
This study supports the use of therapy even in patients with advanced HCV infection as improvements in HAI and fibrosis can be expected. The lack of association between histological response and SVR may support full treatment courses even in individuals who experience a suboptimal viral response at 12 weeks.
Also extracted from the APRICOT database, Soriano et al analysed the rates of SVR achieved with peginterferon/ribavirin in subjects infected with HCV genotype 4. In HCV monoinfection similar, relatively poor SVR rates are seen in genotype 1 and 4 infection. In APRICOT only 7% (60/860) of individuals had genotype 4 and 38% of this group experienced SVR; SVR rates were influenced by baseline viral titre (27% SVR if >800,000IU/ml and 60% if <800,000IU/ml). 
Overall, the SVR rate in those with genotype 4 was similar to the overall rate seen in APRICOT (40%), suggesting slightly higher SVR rates for genotype 4 than genotype 1.
Interferon and HIV replication
Neumann et al studied HIV kinetics in 23 HIV-infected patients coinfected with genotype 1 HCV (mean CD4 cell count 612 cells/mm3) receiving peginterferon alpa-2b and ribavirin for 48 weeks. In the nine subjects with a detectable HIV RNA there was a steady decline in HIV viral load during the first week of HCV therapy and the authors suggest that this is indicative of interferon suppressing de-novo HIV infection; in vitro studies are ongoing. 
Liver biopsy in patients with normal ALT
The question of whether liver biopsy is useful in individuals with normal liver function tests remains controversial. Sanchez-Conde et al performed liver biopsy in 256 HIV/HCV coinfected subjects over a 5-year period. 9.4% had a persistently normal ALT (PNALT) defined as two or more normal measurements within 6 months and their biopsy results were compared with those in individuals with elevated ALTs. PNALT was found to correlate with lower fibrosis scores (p<0.001) but approximately 1 in 4 had significant fibrosis (F2), supporting the use of liver biopsy in patients with PNALT. 
Treatment of acute HCV
Increasing detection of acute HCV infection has raised interest in early treatment. HIV negative individuals have very high rates of HCV clearance, approaching 100%, when treated with standard interferon alone.
A group of 50 gay men attending the Chelsea & Westminster hospital were diagnosed with acute HCV infection (44 during investigation for liver enzyme abnormalities, 4 following sexual contact with an HCV-infected partner and 2 during screening at HIV seroconversion). Sequential HCV RNA measurement was performed at 0, 4,12,24,32 and 48 weeks; 24 weeks therapy with 1.5mcg/kg/week Peg-IFN (alpha-2b) and weight-adjusted ribavirin was offered to subjects who after 12 weeks had a positive HCV-RNA or earlier in the face of a rising RNA level. 
12 individuals became HCV-RNA negative spontaneously; this was significantly associated with a higher median CD4 count (p=0.029), CD4 count >500 (p=0.017) and lower HCV RNA level at diagnosis (p=0.017). Of those offered treatment, 27 accepted and 16 (59%) experienced SVR; SVR was associated with a higher peak mean ALT (p<0.001) but not with genotype.
This study demonstrated a high level of spontaneous HCV seroconversion but lower rates of SVR compared to the results achieved in HIV-negative subjects. The factors associated with spontaneous clearance of HCV-RNA have not been clearly elucidated.
Grebely et al analysed data from the CHASE Project, a prospective cohort study in Vancouver in an area with high rates of injecting drug use. 523/1202 HCV antibody positive subjects underwent HCV-RNA testing between 1991 and 2004. 
Excluding individuals who had undergone HCV treatment previously, the analysis revealed a negative correlation between HIV infection and spontaneous HCV clearance (adjusted OR 0.41; p=0.007). Reinfection was observed in 5.7% of those achieving spontaneous HCV clearance.
Response to HAART in HCV-infected subjects
Although HIV has been shown to accelerate the progression of HCV, a number of previous studies assessing the impact of HCV coinfection on HIV disease have yielded conflicting results. Sullivan et al performed a retrospective, multicentre analysis of patients commencing HAART between 1998 and 2003. They analysed changes in viral load and CD4 cell count to test the hypothesis that viral load reduction during the first 30 days of HAART and CD4 rise during the first year differ in HIV-positive individuals with and without HCV. 
Eighteen per cent of the 1531 subjects included were coinfected with HCV but this was not associated with attenuation of virological or immunological response to HAART; the only patients to experience inferior response to ARVs were those with coinfection and previously diagnosed alcoholism.
The difficulties in assessing the impact of HCV on response to HAART were highlighted by the CASCADE collaboration. Pre-HAART (i.e. pre-1996) data from 22 HIV-seroconvertor cohorts were pooled to assess the effect of HCV on time from seroconversion to death and on virological response to HAART. 
6053 seroconvertors were included, 1405 of whom died. 22%, 25% and 53% were HCV-positive, negative and untested respectively. After adjustment for known prognostic factors, previous ARVs and baseline HIV viral load, a positive HCV antibody was associated with a significantly lower risk of death compared with the untested population (RR=0.18; p<0.001).
2322 individuals subsequently commenced HAART of who 22%, 42% and 36% were HCV-positive, negative and untested. >90% of IDUs were coinfected compared with <16% in other groups, and after adjusting for IDU status there was no effect of HCV on likelihood of achieving an undetectable viral load (p=0.69).
The authors conclude that HCV positivity may contribute to the inferior virological responses seen in IDUs but the high prevalence of HCV in this group makes it difficult to assess accurately.
In another study, Moore et al performed a survival analysis on 721 HIV monoinfected and 673 HIV/HCV coinfected patients initiating HAART between 1999 and 2003. Crude mortality rates were 8.6% and 18.1% in the mono and coinfected groups respectively (p<0.001). After adjustment for age, VL, IDU status and adherence to HAART the baseline CD4 associated with increased mortality were similar for HIV/HCV coinfected individuals compared with those infected with HIV alone. This was interpreted as suggesting no benefit to earlier HAART for HCV coinfected subjects. 
Impact of HCV on HIV
A number of cohort analyses have suggested an increased risk of non-Hodgkins lymphoma (NHL) in HCV moninfected populations. NHL is greatly increased in HIV-infection and a UK cohort analysis examined the relationship between HCV and NHL in HIV-infected individuals. 102 cases of NHL occurred in 5832 HIV-infected subjects but the incidence of NHL did not differ between those with HIV/HCV coinfection and those with HCV alone. 
HAART pharmacokinetics in coinfected patients
In the cross-sectional HEPADOSE Study the Cmin of various ARVs were compared between 66 HIV monoinfected and 73 HIV/HCV coinfected patients. The coinfected group had all undergone liver biopsy within the last 2 years and the groups were matched for sex and antiretroviral agents. 
The median Cmin for protease inhibitors were similar in the coinfected and monoinfected individuals except for Lopinavir (LPV) which was found to be significantly lower in the coinfected group (p=0.04). For NNRTIs, efavirenz/EFV (Sustiva) and nevirapine/NVP (Viramune) concentrations were both higher in the presence of coinfection and these elevations correlated significantly with hepatic fibrosis score; stage F4 fibrosis was correlated with an 86% increase above the expected concentration in NNRTI Cmin and stage F0-3 with a 56% elevation (p=0.01).
In summary, lopinavir levels were unexpectedly decreased and NNRTI levels increased in HIV/HCV coinfected patients; the authors recommend the use of TDM in this population.
However, another analysis of lopinavir/ritonavir (LPV/r; Kaletra) pharmacokinetics, presented by Dickinson et al, quantified LPV concentrations in 39 patients: 13 HIV monoinfected, 26 HBV or HCV coinfected of whom 7 were cirrhotic. The area under the curve (AUC) for both total and unbound LPV levels was unchanged in the coinfected group. 
Safety of ARVs in coinfected patients
Coinfection with HIV and HBV or HCV may increase the risk of ARV-related hepatotoxicity and a number of studies addressed this issue.
The impact of single PI, boosted PI and NNRTI based therapy on liver enzymes in HIV/HCV coinfection was assessed Torti et al. Prospectively collected data from an Italian cohort of 1038 HIV/HCV coinfected individuals was used to construct a multivariate model including ARV history, HBV status, CD4 and VL. 
In naive patients (n=155) the risk of grade 3/4 transaminase elevation was 17.1% per patient year; baseline ALT (HR=1.118; p=0.029) and CD4 increment (HR=1.112; p=0.045) were the only factors significantly associated with hepatotoxicity.
Hepatotoxicity incidence and risk factors differed in experienced patients (n=883). 8.22% per patient year developed grade 3/4 AST/ALT rise; baseline ALT (HR=1.137 per 10 IU/l; p<0.001), previous hepatotoxicity (HR=3.051; p<0.001) and NNRTI use (HR=2.752; p<0.001) were significant risk factors; nevirapine was associated with a greater risk of hepatotoxicity than efavirenz.
The authors advised strict monitoring in ARV-experienced patients with elevated ALT, previous hepatotoxicity or on NNRTI-containing regimens.
In contrast, Konopnicki et al found that PI and NRTI agents but not NNRTIs were associated with hepatotoxicity in HIV-infected individuals with chronic hepatitis. Of the 293, 770 and 488 subjects starting a triple NRTI, PI-based or NNRTI-based regimen respectively, 13% were HCV and 5% HBV coinfected. A >2 grade increase of at least one liver enzyme was more frequent in the coinfected than monoinfected group on a PI (24% vs 12%; p=0.0004) or triple-NRTI (14% vs 4%; p=0.02). 
Multivariate analysis of the PI group revealed chronic hepatitis to be an independent risk factor for hepatotoxicity (OR 1.87; p=0.02) while female sex (OR 0.42; p=0.002) and CD4 >250 cells/mm3 (OR0.47; p=0.004) were protective. Single or ritonavir-boosted PI based therapies were not associated with hepatotoxicity in naive or experienced coinfected subjects.
DeJesus et al presented data confirming the safety of ritonavir-boosted fosamprenavir/ FPV/r (Lexiva) in therapy naive individuals coinfected with HBV or HCV. Subjects coinfected with HBV or HCV could be enrolled into the SOLO study if hepatic transaminase levels were not in excess of 5 x ULN within 28 days of randomisation. 
322 patients enrolled in the SOLO study were randomised to receive fosamprenavir/r and 211 continued into APV30005 (the SOLO rollover); a subanalysis assessed liver enzymes and adverse events. 45/211 (21%) were hepatitis coinfected at study entry, 20 (9%) with HBV (surface antigen positive) and 26 (12%) with HCV (HCV antibody positive).
Median baseline ALT and AST were higher in the coinfected patients but there was a median decrease in liver transaminase levels by week 120 in both patient groups; by week 120 5/164 (3%) of monoinfected and 13/45 (29%) had experienced a grade 3/4 ALT rise; however, only 3 new cases developed in each group after week 48.
Of note, there were two new cases of grade3/4 AST elevation in the monoinfected subjects but none in the coinfected group. Over 120 weeks the numbers experiencing drug-related AEs overall were similar in the two groups. Forty-four per cent of the coinfected individuals experienced a grade 2-4 drug-related AE compared with 43% of those infected with HIV alone; the rates of serious drug-related adverse events were 11% and 10% respectively.
Overall the authors concluded that ritonavir-boosted fosamprenavir administered once daily had similar rates of side-effects in HIV moninfected and coinfected subjects; at 120 weeks there was a median decrease in transaminase levels in both groups.
The safety of abacavir (ABC) plus lamivudine (3TC) based HAART in naive subjects was assessed by Zhao et al in an analysis of 4 randomised trials using ABC/3TC once or twice daily in combination with efavirenz (EFV) or a PI. 
Safety data were compared between individuals coinfected with HBV (positive s-antigen) or HCV and those with HIV monoinfection. Twenty per cent of the 1985 subjects included were coinfected with HBV and/or HCV. Baseline characteristics in the two groups (coinfected vs monoinfected) were similar, as was the overall incidence of AEs with 71% in each group reporting grade 2-4 AEs over 48 weeks. In addition, the incidence of specific AEs was also comparable.
Atazanavir (Reyataz) safety was assessed by Perez-Elias et al by comparing 180 coinfected (Hep) and 124 monoinfected (noHep) prospectively recruited into an early access study of ritonavir-boosted atazanavir (ATV/r) based HAART. 67% Hep and 73% noHep individuals reached at least 6 months of follow-up. 
Similar rates of virological success (<500 copies/mL) were achieved in both groups (approximately 75%) with 9.4% Hep and 5.6% of noHep patients discontinuing treatment secondary to AEs. Only three individuals (1.7%) were withdrawn for elevated liver enzymes.
With respect to scleral icterus and jaundice, 4.4% of the Hep group and 3.2% the noHep group discontinued therapy for this reason. Overall ATV/r-based HAART was concluded to be a safe treatment option for those coinfected with HBV or HCV.
Ammassari et al prospectively monitored transaminase and plasma drug levels in 251 patients commencing HAART. Overall, liver enzyme elevations were more frequent in patients reporting poor adherence and those with suboptimal or undetectable drug levels. No particular group of ARVs was associated with raised ALT though in multivariate analysis, HCV coinfection and duration of ARV exposure were (RR=2.71; p=0.04 for HCV, RR=1.44 per year of ARV exposure; p=0.001). 
The same study showed no difference in hepatotoxicity in patients receiving NNRTIs or lopinavir/r, there was also no relationship between liver enzyme elevations and trough NNRTI levels.
To specifically address the issue of HAART-related hepatotoxicity in HIV/HCV coinfected individuals with advanced liver disease, Aranzabal et al prospectively followed 195 individuals undergoing liver biopsy between 2000 and 2004. 
They found HAART-associated hepatotoxicity to be closely related to HCV-related histological liver damage.
The presence of HBV surface antigen (p=0.01), increased baseline ALT (p=0.04) and longer duration of HCV infection (p<0.01) were associated with more advanced (grade 3-4) fibrosis. Forty-seven per cent of patients developed hepatotoxicity, which, after adjusting for alcohol abuse, was more frequent in those with grade 3-4 than 1-2 fibrosis (5 vs 2.3 cases/100 person years; p=0.02). HIV viral load, CD4, HCV RNA and HCV genotype were not associated with the risk of hepatotoxicity.
In the HEPATOX study presented by Aranzabal et al 246 individuals who started HAART in 2004 were prospectively monitored for hepatotoxicity. No associations with age, sex, risk group, baseline CD4 or CD4 increment were detected and only HCV was found to be independently associated with liver enzyme elevations (RR=3.3; p<0.01). The overall rate of hepatotoxicity was 4% over 100 days. 
Finally, in contrast to the above study, liver disease but not HCV was shown to be predictive of HAART discontinuation by Uberti-Foppa et al. A multivariate analysis of 526 patients commencing HAART found liver disease (low albumin), but not HCV per se, to be associated with an increased risk of stopping therapy. 
Neuropsychological function (NF) in HIV/HCV coinfection
The suggestion that HIV/HCV coinfection may be associated with greater impairment in NF than HIV alone was explored by Munoz-Moreno et al. In a descriptive, observational study of 50 patients (10 coinfected) NF, anxiety and depression scores, premorbid intelligence and contributing HIV-related factors were assessed. A number of differences were elicited between the two groups and HIV/HCV coinfected subjects showed significant impairment in a number of functions compared with their moninfected counterparts. 
ARVs and HCV RNA
In order to determine the effect of ARVs on HCV replication Braitstein et al performed HCV RNA tests on 118 HCV antibody-positive/RNA-negative individuals 6-12 months after commencing ARVs. 20% (24/118) became RNA-positive suggesting that HIV therapy may affect HCV replication with increased replication occurring as part of immune restoration disease. This finding which is difficult to explain needs to be assessed in other cohorts. 
The afore-mentioned study by Benea et al also calculated the prevalence of HBV infection in their HIV cohort. Nearly 40% had at least one marker of HBV infection and 13.53% were surface antigen positive.
Similar rates of active HBV infection (14.8%) were found in a Nigerian clinic by Agbaji et al. This is an important issue in countries where agents active against HBV may not be routinely available. 
A Brazilian HBV/HCV prevalence study found that almost 28% of HIV-infected individuals had not been screened for serological markers of HBV. 45.9% remained susceptible to HBV emphasising the importance of screening for, and vaccinating against, HBV. Likewise, a retrospective analysis in Venezuela found 70% of the 733 screened for HBV to be in need of vaccination.
Vaccination against HBV is established as a safe and efficacious method to protect against acquisition of HBV in high-risk groups. Health care workers are amongst those for whom routine vaccination is usually recommended. A study of health care workers (HCWs) in Uganda found that 74% had not been tested for, or vaccinated against, HBV. A survey of HCWs in Pakistan reported that 60% had experienced one needle stick injury over an average of 5 years but only 50% were HBV vaccinated.
Sud et al confirmed previous analyses showing the success of HBV vaccination in HIV-infected individuals depends on CD4 cell count at time of vaccination. Subjects with a CD4 count <200 (n=13) produced lower titres of sAb than those with a CD4 count >200 (n=27); p<0.05. However, even those with a CD4 count >200 achieved lower titres than HIV negative controls (n=20; p=0.05). 
Impact of HAART on liver-related death
Liver disease has emerged as the most frequent cause of mortality in the HAART-era in a number of studies and a common cause of morbidity in HIV-infected individuals.
Sanchez-Somolinos et al (abstract TuPe1.1C32) performed a retrospective review of hospital admissions in 2514 patients between 1996 and 2004, the majority of whom were IDUs (82%). Decompensated chronic viral liver disease (CVLD) was either the cause of or developed during admission in 14% overall and increased significantly between 1996 and 2001 (9.1% vs 15%) but decreased significantly between 2001 and 2004 (11%). The same was found to be true for liver-related deaths, accounting for 9%, 53% and 23% of mortality in 1996, 2001 and 2004 respectively. Admissions secondary to HAART-related hepatotoxicity increased after 2000. 
Puoti et al performed an analysis of 13 cohorts of HIV/HBV coinfected patients who commenced HAART with liver related death (LRD) as the study end-point. The investigators defined LRD as death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in the absence of other causes, and calculated the impact of lamivudine (3TC) on LRD. 2041 individuals were included in the analysis amounting to 7648 patient years of follow-up on HAART, 5569 of those years 3TC-containing. 
There were 217 deaths during the study period and 57 of these were defined as LRD; 38/57 had information available on previous liver morbidity and 21 (55.3%) of these had experienced DLD or HCC. A model was constructed including the 57 subjects with LRD. The relative risk of LRD per year of 3TC use was calculated to be 0.73 (95% CI 0.59-0.90; p=0.004).
Other factors significantly associated with LRD were age with significantly greater LRD per 10 years (p=0.003) and low CD4 cell count (per 100 cell reduction; p=0.0001). The impacts of other nucleoside analogues (AZT, d4T, ddI and ddC) were analysed and none were found to be associated with the rate of LRD (p-values 0.1, 0.84, 0.97 and 0.28 respectively).
The authors concluded that the use of 3TC within HAART is associated with a reduction in LRD in HIV-infected subjects coinfected with HBV or HCV over a 4 year period but acknowledge that longer-term data are needed to verify this benefit despite the development of the YMDD mutation.
In another presentation, Puoti et al prospectively followed 812 individuals form 1997/1998 amounting to over 4000 patient years of follow-up. 46/129 deaths were liver related and a number of factors were associated including HCV infection (HR=9.2; p=00024), HBV infection (HR=2.7; p=0.0025), alcohol abuse (HR=2.7; p=0.0017), occurrence of life-threatening HAART-related hepatotoxicity (HR=5.8; p<0.0001) and HAART initiation at a CD4 <350 cells/mm3. 
Use of HAART was found to be independently protective against liver related death (HR=0.31; p<0.0001).
The use of 3TC (Epivir-HBV) monotherapy for the treatment of HBV is associated with high rates of 3TC resistance, particularly in HIV/HBV coinfected individuals. In contrast, HBV resistance to the nucleotide analogue tenofovir/ TDF) is uncommon. Whether initial combination therapy with 3TC and TDF is superior to sequential therapy with 3TC then TDF has not been determined.
Mauss et al undertook a multicentre 1:2 matched pair study comparing HIV/HBV coinfected subjects commencing TFV/3TC-containing HAART with patients who had highly replicative, genotypic 3TC-resistant HBV who commenced TFV-based therapy in the absence of other active anti-HBV agents. 
Baseline HBV-DNA was similar in the two groups, 56 million copies/mL and 89 million copies/mL in the TFV/3TC (n=21) and TFV-only (n=42) groups respectively (p=0.96). Both groups experienced similar and strong HBV-DNA suppression at 3 and 12 months. Sustained suppression of HBV-DNA (<1000 copies/mL) was achieved in 18/21 (86%) on TFV/3TC and 33/42 (78%) on TFV alone (p=0.74). HBV e-antigen seroconversion occurred in 6/19 on TFV/3TC and 12/38 on TFV (p=0.77) and loss of s-antigen was seen in 1/21 and 4/42 patients respectively (p=0.66).
The investigators concluded that in coinfected individuals the use of TFV after the development of 3TC resistance was as effective as TFV/3TC in terms of HBV-DNA suppression and e-antigen/s-antigen loss. The durability of these responses will be assessed in continued follow-up.
Ten to eighteen per cent of individuals with HIV/HBV coinfection develop anti-core antibody (HBVcAb) in the absence of neutralising surface antibody (HBVsAb). 955 patients were screened for HBV markers, including HBV DNA in cAb+/sAb- patients, by Marino et al. 19.9% tested positive for cAb alone; 6.9% had detectable HBV DNA (between 102 and 103 copies/mL). Further follow-up showed HBV DNA positivity to be intermittent and to occur in 14.3% of cAb+/sAb- patients over a 6-12 month period. These individuals did not demonstrate clinical or laboratory abnormalities. The authors advise that longitudinal HBV DNA detectability is required to form a diagnosis of occult HBV infection. 
Decompensated liver cirrhosis in HIV-infected patients
A Spanish cohort analysis studied 110 HIV-infected patients who developed Decompensated Liver Disease between 1990 and 2003. Subjects were sub-divided according to date of first decompensation; group A (pre-HAART) 1990-1996 and group B (HAART) 1997-2003 contained 48 and 62 individuals respectively. 
Of the 110, 81% were coinfected with HCV and 34.5% with active HBV. The four commonest initial events were ascites (89%), hepatic encephalopathy (19%), gastrointestinal bleeding (7%) and spontaneous bacterial peritonitis (6%).
Comparison between groups A and B revealed those in group A to be younger (32 vs 38 years; p<0.01), less frequently on ARVs (29% vs 56%; p=0.012) and with lower mean CD4 counts (134 vs 197; p=0.09).
HIV risk factor, cause of cirrhosis, Child-Pugh classification at first decompensation and subsequent complications did not differ significantly between group A and B. Median survival after decompensation was 6 months and significantly associated with Child-Pugh classification.
The cumulative 12-month survival after decompensation was the same for the two time periods, 35% for group A and 34% for B (p=0.85). However, death secondary to liver disease was commoner in the HAART era (81.8% of deaths compared to 60% pre-HAART; p=0.024).
This study confirms the poor survival associated with decompensated liver cirrhosis and highlights the need for rapid consideration of transplant in these patients.
Cicconi et al evaluated the incidence, risk factors and outcomes for decompensated cirrhosis (DC) in the I.Co.N.A cohort. The incidence of DC was 1.85/1000 person years in the 5138 individuals included and not influenced by calendar year after adjustment for other variables. 
Factors associated with an increased risk of DC were IDU (RR=17.31 vs heterosexuals; p=0.0005) and increased age (RR=1.66 per 10 years; p=0.06); different ARVs were not found to influence DC risk. DC was shown to be an independent risk factor for death (RR=8.5; p=p<0.0001) with a median survival of 126 days after diagnosis of DC and a 2-year survival rate of 10.8%.
Hepatocellular carcinoma in HIV/HCV coinfection
Since the huge reductions in HIV-related mortality in the HAART-era, longer-term consequences of coinfection have emerged. HCV is associated with a marked increase in the risk of developing hepatocellular carcinoma (HCC).
A European study previously suggested shorter survival in HIV/HCV infection than HCV alone leading Brau et al to perform a retrospective chart review of HCV-infected individuals with HCC with and without HIV co-infection. Forty-one coinfected HCC cases from 15 US and Canadian centres between 1992 and 2004 were identified and compared with 119 HCV-monoinfected cases during the same period. 
Looking at baseline demographics, 99% of the subjects were male. The median CD4 cell count and HIV viral load at time of HCC diagnosis were 273 cells/mm3 and 529 copies/mL respectively.
The results demonstrated a number of differences between the two groups. Mean age at HCC diagnosis was significantly lower in coinfected than monoinfected subjects (52.4 vs 61.1 years; p<0.001) despite similar ages at HCV infection (25.5 and 23.9 years respectively; p=0.46).
This was mirrored by the duration of HCV infection prior to the development of HCC, 26.4 years in the coinfected group and 35.2 years in monoinfected subjects (p<0.001).
In addition, amongst coinfected individuals, median alpha-fetoprotein (AFP) levels were significantly higher (1274ng/ml vs 192ng/ml; p=0.02), rates of portal vein thrombosis were lower (10% vs 26%; p=0.03) and the incidence of multifocal HCC was higher (58% vs 36%; p=0.011).
The study also found that HIV-coinfected patients were more likely to receive HCC treatment than those with HCV alone (56% vs 36%; p=0.025).
In terms of prognosis the presence of symptoms at diagnosis, HCC therapy and AST/ALT ratio were all predictive of survival in a multivariate analysis.
Elevated AFP levels were only predictive in HCV-monoinfected patients and CD4 cell count and HIV viral load were not associated with survival rates in HIV-coinfected individuals. There was no difference in survival between monoinfected and coinfected individuals (83.2% vs 80.5% mortality respectively).
The risks of viral blood-borne infections from transfusion of contaminated blood are inarguable. Erhabot et al tested 1500 blood donors in Nigeria for HIV, HBVsAg and HCV antibody demonstrating prevalence of 1%, 1.1% and 0.5% respectively; these were higher in remunerated donors (1.45, 1.7 and 0.8%). The authors called for immediate implementation of mandatory and universal donor screening. 
Coinfection with hepatitis viruses in the HIV-infected individual continues to be of concern. Although there has been a rapid increase in epidemiological research on this subject, the practicing physician is still hampered by the lack of choice of agents to treat hepatitis infections and whether the results of clinical trials on the monoinfected patient can be translated into the dually infected population.
As new drugs are developed it is important that they are studied in the coinfected population.
All references are to the Programme and Abstracts of the 3rd IAS Conference on AIDS Pathogenesis and Treatment. Rio de Janeiro, Brazil, 24-27 July, 2005.
Abstracts are available online on the IAS abstract archive:
- Aquino C et al. Identifying proxy indicators for an HIV prevention and harm reduction project in Cebu City, Philippines. Abstract WePe10.4P08.
- Hadi DHMH et al. Incidence of hepatitis C virus and HIV among injecting drug users in Northern Pakistan: a prospective cohort study. Abstract MoOa0104.
- Gabelia et al. Prevalence and risk factors for hepatitis C virus, and HIV infection among injection drug users in Georgia. Abstract MoOa0105.
- Tyndall M et al. Persistently high HIV incidence rates among injection drug users In Vancouver, Canada (1992-2003). Abstract MoPe10.2P08.
- Grigoryan S et al. Initiation of ARV treatment in the Republic of Armenia. Abstract MoPe11.4C01.
- Fay F et al. HCV co-infection among HIV-1 infected persons in an Argentinean province: Distribution of HCV-Genotype in different risk groups. Abstract TuPe1/1C28.
- Lioznov D et al. Prevalence of HIV, hepatitis B and C viruses in high risk population in St. Petersburg, Russia. Abstract TuPe1.1C12.
- Benea E et al. HIV/HCV and HIV/HBV co-infections prevalence in a cohort of Romanian adult patients. Abstract TuPe1.1C33.
- Silva ACM et al. Prevalence of serologic markers of Hepatitis B and C viruses among HIV infected patients in IPEC/FIOCRUZ Rio de Janeiro, Brazil. Abstract TuPe1.1C36.
- Neumann A et al. Early Hepatitis C Viral Kinetics Prediction Of SVR In HIV/Hcv Co-Infected Patients Treated With Pegylated Interferon-Alpha 2B (PEG-LFN) And Ribavirin (RBV). Abstract WePp0304.
- Kruk A. Efficacy of acute HCV treatment with peg-interferon a-2b and ribavirin in HIV infected patients. Abstract TuPe1.1C01.
- Sulkowski M et al. Impact of safety events on sustained virological response (SVR) in patients with HIV-HCV co-infection enrolled in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT). Abstract TuPe1.1C19.
- Lissen E et al. Histological response to peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in HIV-HCV co-infected patients with bridging fibrosis or cirrhosis in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT). Abstract TuPe1.1C21.
- Soriano V et al. Efficacy of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in patients with HCV genotype 4 infection in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT). Abstract TuPe1.1C23.
- Neumann A et al. Differential Anti-Viral Effect of Peg-IFN on HIV and HCV in Treatment of HIV/HCV Co-Infected Patients. Abstract WePe3.3C17.
- Sanchez-Conde M et al. Liver biopsy (LB) findings in HIV infected patients (HIV+P) with chronic C Hepatitis (CHC) and persistently normal Alanine Transaminase (PNALT). Abstract TuPe1.1C42.
- Nelson et al. Is the treatment of acute Hepatitis C in HIV positive individuals effective? Abstract TuPe1.1C10.
- Grebely J et al. Effect Of HIV Co-Infection On Spontaneous Clearance Of Hepatitis C Virus (HCV) In The Downtown Eastside Of Vancouver. Abstract TuPe1.1C18.
- Sullivan P et al. Effect of Hepatitis C infection on immunologic and virologic response among persons with HIV infection initiating highly active antiretroviral therapy (HAART). Abstract TuPe1.1C05.
- Bhaskaran K. The difficulties of investigating the role of HCV coinfection on survival and response to HAART. Abstract TuPe1.1C13.
- Moore D et al. Stratification of risk for mortality by baseline CD4 cell counts in hepatitis C positive and negative individuals initiating highly active antiretroviral therapy (HAART). Abstract TuPe1.1C15.
- Waters L et al. Hepatitis C infection is not associated with systemic HIV-associated non-Hodgkins lymphoma: a cohort study. Abstract TuPe1.1C09.
- Dominguez S et al. The HEPADOSE Study: Evaluation of protease inhibitors and non nucleoside analogue plasma concentrations in HIV/HCV and HIV infected patients. Abstract WePp0305.
- Dickinson et al. The impact of co-infection with Hepatitis C or Hepatitis B on lopinavir pharmacokinetics in patients infected with HIV. Abstract WePe3.2C06.
- Torti C et al. Liver enzyme elevation after singe PI vs. boosted PI vs. NNRTI-based HAART in a cohort of 1038 HCV/HIV co-infected patients: results of the MASTER-EPOKA-a cohort. Abstract TuPe1.1C14.
- Konopnicki D et al. Pattern of hepatotoxicity on different antiretroviral regimens in HIV-patients with or without chronic hepatitis. Abstract TuPe2.1B03.
- DeJesus E et al. Safety of a fosamprenavir/ritonavir (FPV/r) containing regimen over 120 weeks in HIV-1 infected therapy-naive adults with or without hepatitis B (HBV) and/or C (HCV) co-infection. Abstract TuPe1.1C03.
- Zhao H et al. Safety of Abacavir (ABC)+Lamivudine (3TC)-based HAART in ART-naive HIV-Infected Subjects With and Without Hepatitis B (HBV) and/or Hepatitis C (HCV) Co-Infection. Abstract TuPe1.1C16.
- Perez-Elias MJ et al. Effect Of Ritonavir-Boosted Atazanavir (Atv/R) In Experienced HIV-Infected Patients Regarding Chronic Hepatitis B/C Status. Abstract TuPe1.1C25.
- Ammassari A et al. The relative role of HCV-coinfection, adherence to antiretrovirals and plasma drug levels on the incidence of ALT elevation during HAART. Abstract TuPe1.1C29.
- Aranzabal L et al. HAART-associated hepatotoxicity in HIV/HCV co-infected patients with advanced chronic liver disease or cirrhosis. Abstract TuPe1.1C38.
- Aranzabal L et al. Low risk of hepatotoxicity in patients currently starting HAART: The HEPATOX study. Abstract TuPe2.3C25.
- Uberti-Foppa C et al. Impact of progressive liver damage on first HAART discontinuation in HIV-1 infected patients: six year follow-up. Abstract TuPe2.1B04.
- Munoz-Moreno JA et al. Differences in Neuropsychological Functioning between HIV+ and HIV+/HCV+ Infected Patients. Abstract TuPe1.1C35.
- Braitstein et al. Antiretroviral Therapy and the Detectability of HCV RNA in a Population-Based Cohort of HIV-Infected Adults Initiating HIV Treatment. Abstract TuPe1.1C30.
- Agbaji O et al. Seroprevalence of hepatitis B Virus (HBV) and hepatitis C Virus (HCV) infections among HIV-infected patients attending the antiretroviral clinic at Jos University Teaching Hospital (JUTH), Jos. Nigeria. Abstract TuPe1.1C34.
- Sud A et al. Recombinant hepatitis B vaccination in patients with HIV/AIDS: immune responses and effectiveness. Abstract TuPe1.1C41.
- Sanchez-Somolinos M et al. Reduction in liver-related hospital admissions and deaths in HIV+ patients since year 2001. Abstract TuPe1.1C32.
- Puoti M et al. Impact of lamivudine (3TC) on the risk of liver related death (LRD) in 2,041 HBsAg and HIV-Positive individuals. Results of an intercohort analysis. Abstract TuPe1.1C06.
- Puoti M et al/ Impact of Highly Active Antiretroviral Therapy (HAART on liver related mortality. TuPe2.3C27.
- Mauss S et al. Is first line combination therapy of chronic hepatitis B with tenofovir plus lamivudine superior to sequential therapy with tenofovir after resistance to lamivudine in HBV/HIV-coinfection? Abstract TuPe1.1C07.
- Marino N et al. Occult Hepatitis B virus infection in a cohort of HIV infected patients. Abstract TuPe1.1C31.
- Euba G et al. Clinical characteristics and outcome of decompensated liver cirrhosis in HIV-infected patients. Abstract TuPe1.1C08.
- Cicconi P et al. Risk factors for decompensated cirrhosis and associated morbidity and mortality in I.Co.N.A. Abstract TuPe1.1C24.
- Brau N et al. Hepatocellular carcinoma in 40 HIV/HCV-coinfected versus 50 HCV-monoinfected patients. North American HCC in HIV Study Group. Abstract TuPe1.1C17.
- Erhabor et al. The risk of Transfusion-Transmissible viral infections in the Niger delta area of Nigeria. Abstract WePe10.6P01.