Oxford Handbook of Genitourinary Medicine, HIV, and Sexual
Health (2 edn)
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Introduction
Since the introduction of HAART, deaths from HIV, in particular those resulting from opportunistic infection (OI) have markedly ↓. Conversely, liver-related mortality has ↑. Hepatitis B, hepatitis C, and HIV can all be transmitted via blood and sexual contact, and consequently co-infection is common. Assessment of co-infection requires a multidisciplinary approach with attention to ongoing drug and alcohol use, psychiatric illness, progressive liver disease, and degree of HIV immune suppression. Alcohol should be strongly discouraged. Injecting drug users (IDUs) should enter a maintenance programme.
If immuno-naive, hepatitis A/B vaccination should be provided.
HIV–hepatitis B virus (HBV) co-infection
Epidemiology
In high endemic areas of sub-Saharan Africa, Eastern Europe, South and Southeast Asia co-infection rates of 10–15% are found. In the UK, HBV-associated HIV infection is 5–8% with co-infection more common in haemophiliacs, IDUs, and those from high prevalence areas. Co-infection rates vary regionally within the UK.
Natural history and clinical features
Co-infection is usually associated with a higher HBV viraemia and a more rapid progression to cirrhosis. Although HBV does not appear to influence the natural history of HIV, there is ↑ rate of hepatotoxicity in relation to antiretroviral therapy. HBV reactivation can occur in those who appear to have cleared their HBV infection. This can lead to transient HB surface antigenaemia or chronic HBV infection and may occur more frequently when CD4 counts are ↓. In addition the natural clearance of HBe antigen is ↓ but spontaneous recovery from chronic HBV infection may occur in those whose CD4 count ↑.
Diagnosis and investigations
Chapter It is important to repeat HBV serology regularly in immuno-naive patients with HIV infection. Other factors causing liver disease/infection require exclusion.
AFP and liver ultrasound should be performed in all at diagnosis and 6 monthly if cirrhotic. Six-monthly screening should be considered in Asian patients >40 years, African patients >20 years, family history of hepatocellular carcinoma (HCC), and if HBV VL high and ALT abnormal.
If ALT raised, screen for other causes of liver disease.
Liver biopsy is important when active HBV replication (high HBV–DNA, abnormal liver function, or advanced liver disease). HBV genotyping may be considered. Testing for resistance (e.g. YMDD motif codon substitution in lamivudine resistance) should be done if previous treatment or suppression of HBV DNA is not achieved by 6 months.
Fibroscan® has not been validated in HBV infection.
Increased monitoring of liver function on HAART (due to enhanced hepatotoxicity of most antiretroviral drugs).
Management (Box 41.1)
In chronic HBV–HIV co-infection the aim of HBV treatment is to suppress viral replication. Only rarely is it curative (loss of surface antigen). Available treatment options include lamivudine, tenofovir, adefovir, pegylated interferon, emtricitabine, and most recently entecavir.
HBe-antigen −ve patients with normal liver function and low viral load 2000 IU/mL (<104copies/mL) do not require treatment. In these patients, monitor LFTs and HBV VL annually. If started on HAART, avoid lamivudine as only HBV drug. Patients with HBV–DNA >105copies/mL and/or abnormal liver function should have a liver biopsy. Ishak score for fibrosis should be measured: mild disease ≤2; moderate ≥2 to <6; cirrhosis >6.
The optimum time to initiate treatment is unknown. Early intervention may be aided by higher CD4 counts but the risk of emergence of HIV drug resistance must be considered.
Interferon must not be used in HBV-infected cirrhotic patients.
Treatment prior to HAART
Mild liver disease: if HBV VL ≥104 copies/mL, eAg +ve or −ve, and raised ALT, consider treatment with pegylated interferon or adefovir.
Moderate liver disease: if VL ≥104 copies/mL, eAg +ve or −ve, consider treatment with adefovir or pegylated interferon (if ALT raised).
Cirrhosis: if VL ≥103 copies/mL, eAg +ve or −ve, treat with adefovir.
Treatment regime
Co-infected patients requiring HAART should be treated with a regime containing tenofovir and emtricitabine or lamivudine. Lamivudine, tenofovir or emtricitabine should only be used as part of HAART. If HAART regimens containing lamivudine or tenofovir achieve good HBV response, but need to be changed, these agents should be maintained in addition to the new HAART combination. The dose for lamivudine in co-infected patients should be 150mg twice daily or 300mg daily not 100mg daily as in HBV mono-infection.
Assessment for liver transplantation if cirrhosis develops should not be denied.
Initial investigations: CD 4, LFT, hepatitis B viral load
Stage liver fibrosis: ideally by liver biopsy
Decision to treat based on LFTs, liver histology, CD4 and HBV DNA
CD4 >500:
minimal fibrosis, normal ALT and HBV DNA <2000IU/L → monitor 3–6 monthly
minimal fibrosis in Hep eAg +ve +↑ALT, HBV DNA >2000IU/L → pegylated interferon for 12 months.
significant fibrosis → HBV exclusively active agent
CD4 <350 → HAART including agents active against HBV.
CD4 350–500 +significant fibrosis → consider HAART containing agents active against HBV.
HIV–hepatitis C virus (HCV) co-infection
Epidemiology
HCV infection is a major risk for end-stage liver disease (ESLD) in HIV infection. HCV prevalence is much higher in HIV-infected individuals than in the rest of the population (in the UK 5–15% compared with 0.4%). Higher rates are found in HIV-positive haemophiliacs, IDUs, MSM, and those from Southern or Eastern Europe.
Heterosexual HCV transmission is infrequent but may be more likely with anal sex or coexisting STIs.
Natural history and clinical features
Co-infection with HCV accelerates the progression of HIV and results in a poorer CD4 increase with HAART.
HCV-infected individuals co-infected with HIV have a faster progression to cirrhosis if untreated (median time decreases from 32 to 23 years with ~50% cirrhotic at 30 years post-HCV infection) with death from ESLD more common. Vertical transmission of HCV ↑ to 14–17%.
Diagnosis and investigations
Liver biopsy currently recommended except if bleeding disorder present.
Fibroscan® may be helpful, but some evidence suggests overestimation of fibrosis in co-infection if standard cut-off of 12kpa used for cirrhosis.
Monitoring of progression of liver disease with α-fetoprotein, abdominal ultrasound, and Doppler scan of portal vein yearly, and if severe liver disease/cirrhosis 6 monthly. Monitoring should continue if severe liver disease after successful treatment.
Increased monitoring of liver function on HAART (because of enhanced hepatotoxicity of most antiretroviral drugs).
Management (Box 41.2)
Treatment should be considered in all patients but can be difficult with ↑ side-effects in the co-infected. Pre-treatment investigations as above with TSH, FBC, U+Es, LFTs, and CD4 count.
Pre-treatment
Consider the following:
HAART should be started if CD4 <350cells/μL and HCV treatment should be delayed until CD4 has increased >200cells/μL (treatment success improves with ↑ CD4 percentage >25%). A temporary CD4 drop of up to 150cells/μL occurs on interferon; percentage is normally preserved.
Didanosine and Zidovudine should be avoided in combination with ribavirin (increased SE). Abacavir may lead to ↓ response.
Treatment regime (Box 41.2)
Non-cirrhotic: pegylated interferon 2α (180mcg/week) or pegylated interferon 2β (1.5mcg/kg/week) + ribavirin (<75kg 600mg + 400mg; >75kg 600mg bd).
Cirrhosis: increased side-effects. Seek specialist advice—escalating dose regime may be necessary.
Ophthalmology review if hypertension or diabetic—increased retinal disease with interferon
Treatment should be monitored with 2 weekly and then monthly FBC, LFTs, 3 monthly TFTs and CD4, and HCV viral load at 4, 12, 24, and 48 weeks. Responders are HCV RNA −ve at 12 weeks post-treatment. Further RNA should be checked to confirm.
Side-effects ↑ in co-infection, particularly haematological disturbance. Consider erythropoietin to maintain ribavirin dose particularly in early stages up to week 12 of treatment.
Treatment length
Genotypes 2 and 3:
48 weeks if HCV RNA −ve at week 4: consider 24 weeks treatment particularly if poor tolerance
Genotype 1
HCV RNA −ve at week 4: 48 weeks treatment
HCV RNA +ve week 4, >2log drop week 12 and −ve week 24: consider 72 weeks treatment.
Acute HCV (new HCV Ab +ve when previously −ve): treat within 6 months of infection with HCV.
24 weeks with VL at 12 weeks.
Interferon should be stopped if HCV RNA +ve at week 12 in all
genotypes as sustained virological response <1% at end of
treatment.
Patients with genotypes 2 and 3 and mild/moderate liver disease have a sustained viral response of ~60%. Patients with genotype 1 have a sustained viral response of ~30% at best (48 week regimen). Patients must be warned that virological response does not lead to immunity to HCV and transmission may recur with resumption of high-risk activity.
Those with stable HIV disease requiring liver transplantation should not be denied assessment although current experience is small.
Baseline tests+ LFTs, HCV genotype, HCV RNA, CD4.
Liver fibrosis assessment: ideally liver biopsy (not required for genotype 2 and 3) if available fibroscan or fibrosis biomarkers.
CD4 >350 → treat as for HCV mono-infection.
CD4 <350 → HAART + pegylated interferon + ribavarin (consider drug interactions and toxicity).
During treatment measure HCV RNA at 4, 12, 24 and 48 weeks.
Duration of treatment:
24 weeks for genotypes 2 and 3 if rapid virological response achieved, otherwise 48 weeks if RNA −ve at 24 weeks
48 weeks for genotypes 1 and 4 but extend to 72 weeks if >2log RNA drop at 12 weeks and RNA −ve at 24 weeks.
