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HIV and hepatitis in non-injecting drug users

Published: 19 January 2006

Wherever HCV is found in a significant proportion of the general population, it is often the result of a mass inoculation programme where vaccination devices were used repetitively without proper sterilisation.

For example, Egypt has the highest rate of HCV in the world (around a third of the general population) because HCV was spread by mass intravenous anti-schistosomiasis inoculations in the 1960s-70s (Deuffic-Burban). Studies suggest that small-pox inoculations had a similar impact in Pakistan (Aslam).

But even in these situations, HCV infections tend to be clustered by age group (depending upon when the unsafe vaccination programmes took place). For example, a study of one rural village in the Nile Delta reported that by far the highest HCV seroprevalence (of more than 40%) was detected in males aged 40-54 years (Arafa).

HCV may be more difficult to contract than HBV, but the consequences are more likely to be serious regardless of how the infection occurs. Approximately 40% of those infected with HCV are likely to go on to develop some form of liver damage, with liver cancer and liver failure the most serious consequences of HCV infection. The risk of developing liver damage increases with the duration of infection, and is seriously exacerbated by alcohol consumption. The average time from infection to development of cirrhosis of the liver is between 30 and 40 years in HIV-negative people, which is why the public health consequences of HCV infection are still poorly recognised in most countries.

HCV is frequently restricted to isolated risk groups so there are also dramatic differences in the HCV prevalence among different cohorts within the same country. Madhavaet al reviewed data from 160 different cohorts in sub-Saharan Africa, and the HCV rates ranged from 0-40%. The highest rates and widest ranges were reported in Cameroon and Burundi, but even once these outliers were excluded, the prevalence ranged between 0-17%.

It’s generally agreed that injection drug use has not made major inroads into Africa, although transfusions may contribute to the spread of HCV there (few Africa countries consistently screen the blood supply for HCV). Some HCV transmission may come from unexpected sources such as tattooing, scarification, piercing, circumcision or other ceremonial, traditional medical or cultural practices involving blood-blood exposure.

Scale of co-infection

In countries where HBV is not endemic, studies have demonstrated a very high prevalence of HBV in people with HIV. This is likely in those settings because both viruses are transmitted by “high risk” behaviour (most frequently unprotected sex).

But in countries where HBV is endemic, the association between HIV and HBV infection is not as great — though it may still exist. Several studies in Africa suggest that active HBV may roughly twice as common in people with HIV as in the general population (Burnett).

In the case of HCV, the burden of coinfection depends on which behaviours are driving the HIV epidemic locally. If HIV is spread primarily by sexual or perinatal transmission, HCV should generally be found in relatively the same frequency of people with HIV as in the general population (Madhava); but where HIV is contracted mostly from exposure to infected blood (due to injection drug use or transfusions), there is a very good chance of encountering HCV in the same patients.

For example, in the Russian study mentioned above, 93% (214/230) of HIV-positive IDUs were found to be coinfected with HCV. Similarly, in a study of the 236 HIV-infected individuals in China (63% of whom were blood/transfusion recipients or IDUs), 57% were coinfected with HCV (Zhang).

But given regional variations for both HBV and HCV, it pays to know the local prevalence of both chronic HBV and HCV and to be aware of local cultural practices that might be associated with a higher HCV prevalence. This may require improved surveillance for both HBV and HCV in local populations.

Impact of coinfection on disease progression

The majority of cohort studies show that coinfection with HIV and HCV accelerates liver damage caused by HCV and individuals with both HCV and HBV in addition to HIV have a higher risk of death than HIV-positive people coinfected with only one hepatitis virus (Bonacini, Salmon-Ceron).

People with HIV who become HBV infected are more likely to develop chronic hepatitis, and rates of HBV and HCV viral replication are higher in people with AIDS.

Also, this ongoing HBV/HCV replication may not immediately be associated with detectable symptoms, because AIDS partially suppresses the inflammation that mediates liver damage.

This is important, because liver function tests may not identify a person with AIDS and HBV or HCV infection that is not detectable by standard tests (occult infection) who has yet to start ART. In the absence of a liver biopsy, liver disease may only become evident following a liver enzyme elevation once ART is started.

Impact of coinfection since ART

Since the introduction of ART, liver disease has become a more common cause of death in people with HIV (Mocroft) (see http://www.aidsmap.com/en/news/45AB11EA-F29C-48E1-9B50-FBC6D9C20110.asp). One researcher found that since ART, HIV / HCV coinfected individuals were approximately twice as likely to be hospitalised and three times more likely to die compared with HCV-negative individuals with HIV alone (Klein). Another recent study found that HCV coinfection increased the risk of death amongst HIV-positive US veterans by between 30% and 80% (Backus). A meta-analysis presented at a United States National Institutes of Health consensus conference on hepatitis C in June 2002 showed that HIV / HCV coinfected people had a two-fold greater risk of cirrhosis and a six-fold greater risk of end-stage liver disease than those with HCV alone (National Institutes of Health 2002).

Again, the increase in morbidity and mortality related to liver disease among HIV-positive people since the advent of ART is due in part to the fact that individuals receiving effective anti-HIV treatment are much less likely to die from other causes. In addition, as coinfected individuals live longer, there is more time for progressive liver damage due to chronic hepatitis B or C to develop.

Furthermore, “flare-ups” of hepatitis in people on ART can be due to immune reconstitution inflammatory syndrome — a potentially deadly reaction to an HBV or HCV infection (which was previously occult). This is most common in the people with advanced HIV, with very low CD4 cell counts or CD4 cell percentages (Sherman and Ratnam).

Finally, a proportion of liver-related adverse events and deaths in people with HIV may be due to hepatotoxicity associated with antiretroviral drugs or with other hepatotoxic drugs such as isoniazid. This is most common when chronic HBV or HCV has not been identified before starting ART (and when liver function has not been monitored closely enough in such patients).

In the various studies that have been performed, it is difficult to ferret out whether drug toxicity, IRIS, or simply the relentless progression of liver disease due to chronic HBV or HCV is the cause of more hepatitis in people on ART.

Several other factors also confound interpretation of the studies:

  • Heavy alcohol use by a person with chronic hepatitis greatly increases the risk of cirrhosis and liver decompensation and is common among some HIV-infected populations.
  • There could be dangers associated with mega-doses of vitamins or other supplements (http://www.aidsmap.com/en/news/DB3DF39C-B2ED-48B5-9F53-CD698E0F6337.asp)
  • People on ART are frequently also taking other medicines that are toxic to the liver.

For example, in one recent study in JAIDS, researchers from Chennai, India reported hepatitis in 33 out of 1184 people put on a nevirapine-based regimen which led to a treatment switch (Kumarasamy) (see http://www.aidsmap.com/en/news/DFE0AD54-F746-47B9-A490-B08190959082.asp). 27(82%) of these cases were also concurrently on rifampicin-based anti-TB medications. This is curious, because rifampicin significantly lowers blood levels of nevirapine — and thus one should be less likely to observe nevirapine-induced toxicity. Furthermore, these individuals had fairly low CD4 cell counts (~65 at baseline)— and nevirapine-induced hepatitis typically occurs in people with higher CD4 cell counts (over 250). So it seems quite possible that the toxicity may have been due to the TB regimen, to IRIS (no information was given on whether HBV or HCV were screened for) or possibly to an as of yet unidentified synergistic toxicity between nevirapine and rifampicin (which are not commonly prescribed together because of the effect on nevirapine drug levels). 

Benefits of ART in coinfected patients

Such events only serve to reinforce misconceptions about the safety of ART in patients with impaired liver function and hepatitis. Reports of an increase in adverse events and liver disease in people with HIV since the advent of ART are the likely cause for misinformation such as that quoted at the beginning of this article. But a number of recent studies confirm that, on the whole, people coinfected with HIV and one of the liver viruses are better off taking ART.

For example, a study in the January 2nd 2006 issue of AIDS reported that mortality fell in HIV/HCV coinfected people in the years after the introduction of effective HIV treatment (Lumbreras) (see http://www.aidsmap.com/en/news/9ECCC721-86FB-4341-BEB4-0AABB84A1A61.asp); while a study in the January 15 issue of Clinical Infectious Diseases found that progressive liver damage from chronic hepatitis C is much less common in coinfected people when they are taking effective ART (Verma) (see http://www.aidsmap.com/en/news/4658A9C0-D5DC-4E08-BCCB-05D9F466C249.asp). Similar data has been reported for people with coinfected with HIV and HBV (Konopnicki) (see http://www.aidsmap.com/en/news/9434925B-C63E-49A4-AF95-01B5CA7F4AF7.asp).

Considerations before using ART in people coinfected with HBV or HCV

While ART should not be deferred simply because a person with HIV also has HBV or HCV, there may be a number of ways to optimise his or her response to therapy.

These are:

  • Monitoring liver function to identify individuals with poor liver function
  • Screen for HBV and HCV
  • Treat chronic HBV with an antiviral drug or include a drug active against HBV in the anti-HIV combination
  • Treat the hepatitis C infection where resources permit
  • Choose antiretrovirals to minimise the risk of liver toxicity

Monitoring liver function

Liver function tests (LFTs) are good indicators of liver disease in some patients, though not all (particularly if they have occult HBV or HCV).

Traditionally, a liver profile would evaluate alanine amino transferase (ALT/SGPT) and aspartate aminotransferase (AST/SGOT). Both these tests look for enzymes which are usually present in liver cells, but may leak out into the bloodstream when liver cells become damaged. ALT  is thought to be a more accurate measure of liver damage, as AST can be produced by other organs such as the heart.

The normal range for both ALT and AST is 5-40 IU/L (International Units per Litre). Minor elevations in ALT and AST (up to three times the upper limit of normal level) are common in people with HIV, particularly those with advanced disease. The reasons are numerous but could include drug therapy, alcohol or malnutrition. But elevations greater than 3 times the upper limit of normal suggest hepatitis.

The safety of a treatment may depend on how closely it is monitored and there is a range of opinion as to how close laboratory monitoring of antiretroviral therapy needs to be in resource-constrained settings.

In  some settings, LFTs are only checked at baseline before putting people on ART and then not again until six months later. In the study in Chennai, the median time to development to hepatotoxicity was 34 days, which led its authors to conclude “in light of our data, however, earlier laboratory monitoring for toxicity is advisable.”

Screen patients for HBV or HCV

Where resources permit, baseline lab tests for HBV and HCV could help identify which patients might benefit from closer monitoring on ART. 

A negative hepatitis B surface antigen (HBsAg ) and core IgG antibody test results can also identify a patient who is at risk of acute HBV (and may be an indication for anti-HBV vaccination). 

Where resources do not permit screening for HBV or HCV, detailed history taking, clinical screening and an assessment of the local populations risk for either virus could help identify patients likely to have chronic HBV or HCV and to guide the frequency of liver function tests.

Consider treatment for chronic HBV

The anti-HIV drugs lamivudine (and the similar emtricitabine (FTC)) and tenofovir are active against hepatitis B and could be considered as part of an ART regimen. As a treatment for hepatitis B, lamivudine results in viral clearance in about 20-30% of people after one year. It may be possible that therapy longer than one or two years is required.

Around 20% of people experience a hepatitis flare-up when they stop taking lamivudine. This may lead to a rebound in hepatitis B DNA in around 20% of patients, and in a small minority (2-4%), to increased ALT and bilirubin levels.

Prolonged use of lamivudine (3TC) in individuals with hepatitis B as the single agent that is active against HBV leads to resistance in about one third of individuals. However, there is evidence that 3TC-resistant hepatitis B remains sensitive to adefovir and tenofovir. Studies have also shown that 3TC plus tenofovir reduces HBV viral load more effectively than 3TC alone.

A study last year reported such flare-ups of hepatitis despite the inclusion of 3TC in two patients who showed no evidence of 3TC-resistant HBV (Drake). The authors emphasised the need to “maximally suppress HBV replication from the outset.”

The authors recommend that combination therapy with lamivudine plus tenofovir “should be employed at least for cirrhotic patients at risk for hepatic decompensation and, perhaps, even for all coinfected patients with HBV replication.” (see http://www.aidsmap.com/en/news/75BDBF2F-8218-4D60-A983-2A2F11AC12D6.asp).

However, at this point, tenofovir’s role (or importance) in the treatment of HIV in resource limited settings is uncertain — and thus it may be too soon to follow this recommendation without further study.

And for HCV?

While middle income countries may be able to treat patients with intravenous alpha interferon combined with ribavirin (which is available generically), this form of treatment is both too expensive and impractical to employ in the many resource-constrained settings. In such places, ART and palliative care represents the only and best way to care for chronic HCV in HIV coinfected patients for the foreseeable future.

Choose antiretrovirals to minimise the risk of liver toxicity?

Although cohort studies in the developed world repeatedly show that coinfection with HBV or HCV is the most important risk factor for liver toxicity, the association between particular antiretrovirals and liver toxicity in people with hepatitis coinfection is hard to pin down.

For example, nevirapine is associated with liver toxicity in individuals with higher CD4 cell counts, but that toxicity seems to be a classic liver toxicity rather than one driven by hepatitis or decreased liver function. Nevirapine’s manufacturer has reported no greater frequency of liver toxicity in people who receive nevirapine in clinical trials when compared to the control group, and an Italian cohort study published last year found that high baseline liver enzyme levels were the only predictor of liver toxicity (http://www.biomedcentral.com/1471-2334/5/58).

More stringent monitoring rather than denial of treatment or avoidance of particular drugs seems to be the most appropriate course to take where hepatitis coinfection is known or suspected, most experts agree.

Further information on hepatitis B and C

Hepatitis B overview

http://www.aidsmap.com/en/docs/5C509E1C-7894-4D63-99DA-8A12BD47D1E4.asp

Hepatitis C overview

http://www.aidsmap.com/en/docs/BE313493-C188-4F68-BE63-D5F180CCD6FE.asp

Hepatitis news stories

http://www.aidsmap.com/en/news/C8B61025-2693-435B-9CEA-648878CD1800.asp

Patient information

Future Issue:

HATIP poses the question of how best to manage chronic hepatitis in HIV infected patients to our advisory panel shortly for a further exploration of this subject.

References

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Backus LI et al. Effects of hepatitis C virus coinfection on survival in veterans with HIV treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 39: 613-619, 2005.

Bonacini M et al. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS 18: 2039-2045, 2004.

Browne R et al. What is your patient taking? Dietary supplements in a HIV-positive patient. International Journal of STD and AIDS 16: 639 – 641, 2005.

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Zhang L et al. Molecular Characterization of Human Immunodeficiency Virus Type 1 and Hepatitis C Virus in Paid Blood Donors and Injection Drug Users in China. J Virol. 78(24): 13591–13599 2004.

HATIP #61, 19th January, 2006

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.