Many individuals infected with HBV at birth or during early childhood and subsequently infected with HIV have asymptomatic HBV chronic infection with or without aminotransaminase elevation. Patients who develop acute hepatitis B during their adulthood will have abrupt and progressive jaundice with GI symptoms such as nausea, abdominal pain, flatulence, and bloated abdomen. The general symptoms include fatigue, dizziness, weight loss, or anorexia. The liver is usually not enlarged, and the cutaneous stigmata of chronic liver disease is not detected unless the disease has progressed to decompensated cirrhosis. Cirrhosis is more common in patients with lower levels of ALT and CD4 compared to those monoinfected with HBV [31
]. HIV-HBV co-infected men are much more likely to die of liver-related causes compared to monoinfected HBV patients [33
]. The risk of HCC is somewhat increased in HIV-infected individuals with low CD4 counts [34
]. Patients with genotype C have exhibited earlier progression of cirrhosis and HCC than those with genotype B [17
Similarly, patients co-infected with HCV and HIV have asymptomatic acute HCV infection. It is also possible that many IDUs co-infected with HCV and HIV may not have reported their symptoms, and this may not necessary reflect an accurate account of HCV infection among these groups of people. Usually, in non-IDUs, acute hepatitis C is detected in PLWHAs currently on treatment and diagnosed with sexually transmitted infections (e.g., syphilis, gonorrhea) because of elevated enzyme levels. HIV positive individuals with acute HCV infection can develop chronic HCV infection. In contrast to HBV, in HCV co-infected patients, disease progression to liver cirrhosis and hepatocellular carcinoma (HCC) occurs very quickly and may exist prior to HCV treatment. As a result of this, physicians need to closely monitor these patients, even those that have sustained viral response to HCV treatment. Routine HBV and HCV screening are not routinely performed at tertiary care setting. Many HIV patients with undetectable HIV RNA and elevated liver enzymes are screened for hepatitis and eventually found to be co-infected with HBV [14
Currently, the national guidelines for antiretroviral therapy in HIV-infected adults and adolescents in most countries recommend HIV-infected persons to be screened for HBV before initiating ART. The reason for this is because this will help guide physicians in designing the patient's HAART regimen which should contain at least 2 antiretroviral drugs with activity against both HIV and HBV, that is, tenofovir plus lamivudine or tenofovir plus emtricitabine. The viral hepatitis serology is widely available but not routinely used to screen those patients most at risk such as IDUs and MSMs. Tests for HBs antigen are recommended to all HIV-infected patients, but recently, in actual practice, 55–69% of HIV-infected adults were tested for hepatitis [12
]. Asymptomatic chronic infected cases are not unmasked and may continue to transmit the viruses through contaminated blood and genital secretions. If HIV-infected people are aware of the effects of HBV and the accessibility of HBV treatment, then the rate of HBV screening prior to ART may improve. The results of HBV serologic profiles are interpreted as mono-HBV infection (see ). However, isolated positive core antibodies are more frequently (20–30%) found in co-infected patients [37
] compared to those monoinfected with HBV, especially in advanced immunocompromised [38
], HCV co-infected cases [39
], or IDUs. The clinical significance of having a positive anti-HBc antibody is not well understood, but there is more evidence indicating that people with this serologic finding has an occult infection with frequent hepatic flares [42
] and potential of transmitting the infection [43
]. In certain cases, some may have undetectable HBV DNA with isolated core antibody [47
Findings and interpretations of HBV serologic markers.
Since HBV/HIV co-infection is common, it is highly recommended that in every HIV-infected individuals, serologic screening tests for hepatitis B should include HBs Ag, anti-HBs, and anti-HBc antibody. If all 3 serologic tests are negative, then it is highly recommended that the patients get a hepatitis B vaccine to prevent infection. If an isolated core antibody is detected, then a confirmatory HBV-DNA or complete liver function workup is needed to help guide the patients' long-term care management. It is not conclusive whether HIV-infected individuals with isolated core antibody should get a Hepatitis B vaccine. The vaccination may have a primary or an amnestic response [37
]. If HBs antigen is positive, then it is important to assess whether the patient also has HBe Ag, anti-HBe antibody, HBV-DNA and liver enzymes to rule out viral replication, liver complications and whether treatment is needed.
Majority of patients presenting acute HBV infection will have elevated levels of liver enzymes (ALT > AST with >10 times ULN). However, as for those currently infected with HBV or have tested positive for HBs antigen, it is difficult to differentiate whether they are HBV carriers or have chronic infection with low or nonreplicative phase. In healthy carriers, HBV-DNA may not be detectable because of transient viremia and therefore would require retesting. HBV-DNA is somewhat useful but is too expensive for some countries with limited resources. Certain places may not have access to machines to detect HBV-DNA, and some patients may not be able to afford such diagnostic tests. In order to detect and differentiate chronic active HBV patients from positive serostatus for HBe Ag, physicians would need the patients' medical history, risk behaviors or predisposing factors, and physical findings such as stigmata of chronic liver.
Liver enzymes can be used as a surrogate marker for detecting hepatic necroinflammation, but its elevation may also indicate a hepatic flare from any causes including the virus itself. Serum aminotransferase levels are less reliable in determining whether the patient would need therapy or not. Serum aminotransferase levels can be lower in patients co-infected with HIV and HBV or within normal range in some patients with significant hepatic fibrosis. Even though liver pathology can specifically detect fibrosis and necroinflammation by using a scoring system; however, its procedure is invasive, time-consuming and may not be sensitive if there is bias in the way the samples are collected or assessed. Assessing the extent of the underlying liver damage is important because it will affect the prognosis of the infection as well as the choices for treatment. Another noninvasive test known as the hepatic elastography (Fibroscan) can be used to measure the liver's stiffness or evaluate hepatic fibrosis. The results from the Fibroscan can guide treatment and care but may not be possible in resource-limited settings. Some of the limitations of the fibroscan are its inability to accurately predict the degree of injury seen on a liver biopsy or subsequent clinical events. Close monitoring is necessary to detect early cases.
In regards to HCV co-infection, the national guidelines recommend to screen for anti-HCV antibody before initiating ART in HIV-infected adults exhibiting symptoms or those with risk factors such as intravenous drug use. The treatment cost for HCV is extremely expensive and is not covered by the national health schemes. Patients with HCV who need treatment must pay for their own treatment. Aside from that, the national health schemes do not provide free diagnostic tests for HCV genotype and HCVRNA load. At the present, in majority of the countries, there is insufficient epidemiological data on HIV/HCV co-infection. Hence this may be one of the reasons why the national health schemes will not offer free HCV testing in HIV-infected individuals. According to the physicians who have done anti-HCV tests in their HIV-infected patients, there is a high prevalence of HCV co-infection. This result indicates that an appointed committee should include HCV tests in the national guidelines for HIV-infected patients.
It is possible to use tests to detect for anti-HCV antibody to screen those groups at risk for acquiring the infection. However, it is important to note that anti-HCV seroconversion occurs much slower in HIV-infected patients, and it is still possible to have anti-HCV negative results despite ongoing viral replication for a year [49
]. Currently, HCV antibody tests cost around 6–9 USD. In a resource-limited setting, this cost is affordable yet it is not included in the national health care program. This test can be used to screen and diagnose HCV in HIV-infected patients even though it may not be perfect. It can be used in clinical settings or as requested. In most of the cases, there are no or very little clinical symptoms as seen in people with acute HCV infection. Therefore, acute HCV infection is defined as having detectable HCV-RNA in the first 6 months after infection. Transaminase levels can also be used to accurately detect acute HCV infection. Elevated levels of alanine transaminase (ALT) are more sensitive in detecting acute HCV when compared to anti-HCV antibody tests. Tests to detect HCV-RNA are used to determine the virus's replicative state. Hence results from HCV-RNA tests can detect early infection better than the antibody tests and are usually used to exclude false positive results obtained from the serologic tests when the patients have disclosed not having any risk behaviors. Sometimes it is also used to determine whether the result from the serology test is a false positive or not. Past resolved HCV infection may yield false positive results in the serology test. HIV positive individuals who need to start antiviral treatment should be screened for HCV by using the HCV-RNA tests and monitored regularly [50
]. Chronic hepatitis C infection is defined as having ongoing viral replication for more than 6 months. Without the patient's past hepatitis C test results, it is difficult to determine the HCV status of the patient based only on the patient's history, current physical and laboratory examinations. It is very difficult to distinguish between acute and chronic infection because flares during chronic hepatitis C may mimic acute infection.
Genotyping should be done in every case who will need HCV treatment because this will help guide the physician in determining the length of treatment, predict treatment response and prognosis of HCV (see ). However, if genotyping tests are not available, then physicians from resource-limited setting can use regional epidemiological data to determine the subtype of HCV. As for those patients not on HCV treatment due to no indication, treatment intolerability or failure and drug availability, it is important to continue to monitor and assess the progression of the disease. Liver enzymes should regularly be checked every 3 months and repeated if there are significant elevations. The degree of histologic injury is a better predictor of subsequent clinical events than is the degree of elevated serum aminotransferase levels, genotype, or viral load. The result of the Fibroscan can support the physician's decision to start or defer treatment with a higher level of confidence. CD4 cell count appears to be a good predictor for spontaneous clearance [51
]. Antiretroviral treatment may help to control HCV if HCV treatment is not provided. Thrombocytopenia and reversed albumin/globulin ratio can be detected in cases with progressive liver cirrhosis in patients with hepatitis C. Also, serological markers correlated with stages of liver fibrosis can be used with indices obtained from routine blood tests to determine the function of the liver (e.g., APRI (aspartate aminotransferase [AST]-to-platelet ratio index) and Fib-4 (age, AST, platelets, and ALT level)). Alpha feto-protein (AFP), a tumor marker for hepatocarcinoma, can help interpret liver images whereas pathology can confirm the stage of the disease. Screening for hepatocarcinoma should include ultrasound of the liver and serum AFP should be performed every 6 months for all chronic hepatitis B and C patients with cirrhosis. However, according to the systematic reviews, AFP is not considered sensitive (73.5%) [52
] and has no existing correlations in hepatocarcinoma [54
]. This serves as a warning sign that more needs to be done to prevent the transmission of the virus as well as increase the community's awareness of comorbidity among hepatitis co-infected patients.
Figure 1 Treatment scheme for HCV coinfection guided by genotype and HCV-RNA load assessment at baseline, wks 4, 12, and 24 [48, 72].*Patients having baseline HCV-RNA load <400,000IU/mL with minimal fibrosis.
In conclusion, routine screening using serologic tests for hepatitis B and C is beneficial for the patient to determine when to start treatment or those who cannot afford such care to closely monitor the disease progression and complications. The use of stavudine, didanosine, and nevirapine, which are unfriendly to the liver, should be used with caution because it can lead to liver toxicities. For public health concerns, this will also help reduce the risk of transmission if treatment is provided and reduce risk behaviors. As for those at risk of acquiring hepatitis such as immunocompromised patients, physicians can recommend HBV vaccinations. It is highly recommended that in resource-limited settings where there is a high prevalence of hepatitis, HBV and HCV should be screened in HIV-infected patients prior to ART.