The Triple Challenge
Treating Patients with HIV, TB and Hepatitis C in China
By Eric Goosby, MD, CEO, Chief Medical Officer and Deborah von Zinkernagel, RN, SM, MS Pangaea Global AIDS Foundation
In parts of Southeast Asia and Central Europe, the scale up of HIV treatment takes place within overlapping epidemics of TB and hepatitis C (HCV), particularly in populations where injection drug use and poverty are widespread. The presence of all three infections creates conditions for a perfect storm in medical management, as treatments for TB and HIV each affect the liver already weakened by HCV. In the southwest provinces and some areas of central China, for example, many patients present with all three infections, leading to unique challenges in their medical care. The effects of co-infection also ripple across the health system influencing the selection of ARV regimens and requiring closer monitoring for drug toxicities as well as training approaches that emphasize clinical judgment over standardized protocols.
HIV/AIDS, Tuberculosis and Hepatitis C in China
An estimated 650,000 persons are living with HIV infection in China. The largest proportion of these, 44.4 percent, were infected through injection drug use, (IDU) and another 10.6% infected by transmission through unsafe blood collection and transfusion practices. The epidemic has also spread among sex workers, some of whom are also at risk due to IDU.
The HIV epidemic among injection drug users is most severe in the southwestern region bordering the “Golden Triangle” where Burma, Laos and Thailand come together and annual heroin production and trafficking is very high. The common practice of needle sharing is a risk factor linking the spread of both HIV and HCV. A significant proportion of HIV+ patients are co- infected with HCV and a lesser number with hepatitis B (HBV).
HIV and HCV co-infection are also common in some provinces in central China where poor farmers and peasants were paid for blood donations, but unsafe collection and transfusion practices resulted in rapid spread of HIV and HCV among donors, their spouses and sexual partners. A study of several rural communities in Shanxi province found 85 percent of HIV+ villagers to be co-infected with HCV.
China is one of 22 high TB burden countries in the world. Similar to the demographics of HIV, the prevalence of TB in poorer rural areas is nearly twice that in urban areas. Multi-drug resistant TB is a serious threat, with roughly one quarter of the world’s MDR-TB cases occurring in China.
Challenges Posed by Co-Infections
Diagnostic challenges
As seen in other regions, there are often diagnostic challenges in China in confirming TB in persons with HIV. China’s national protocol for TB requires a positive AFB (acid fast bacillus) smear for the diagnosis of pulmonary TB, except in those cases where a chest x-ray is conclusive. Taking a TB culture is not an option in most facilities, which lack the lab capacity to do this test. AFB smears are widely available and used to confirm a TB diagnosis, although studies have found that up to 40 percent of HIV+ patients with pulmonary TB are AFB-smear negative, even when x-rays are suggestive of TB. This poses a challenge to clinicians in China who note constitutional symptoms (fever, night sweats, cough, and weight loss) in their patients but are unable to confirm the likely diagnosis of TB. At present public funds do not cover patient costs for TB treatment unless the diagnosis is backed by clear cut lab findings or definitive xrays.
As many HIV+ patients who have TB symptoms without confirmatory diagnostic tests respond favorably to TB medicines, i.e.the symptoms go away and the patient regains health, new guidelines are being explored to address this diagnostic challenge. In early 2006 the Chinese ministry of health held a technical workshop in Beijing to develop clinical algorithms, or protocols, that would inform a government standard for diagnosing pulmonary TB when AFB smears are negative, and to update guidelines for the diagnosis of extrapulmonary TB.
Potential for Liver Damage
Hepatitis C is a chronic illness for which recommended therapies such as interferon preparations and ribavirin are very expensive and inaccessible to most patients. Studies have shown a twofold risk of progression to cirrhosis and a six-fold risk of progression to liver failure in those who are co-infected with HIV, compared with those infected with HCV alone. Other clinical considerations for patients with HCV in China, include the common use of a traditional Chinese medicine known as “liver protection medicine” and the widespread social use of alcohol that can further exacerbate liver damage caused by HCV infection. Counseling and support to help patients reduce their alcohol consumption becomes an important message for individuals taking ARVs or TB medications.
Hepatitis C alone, in the absence of other co-infections, commonly causes fluctuating patterns of liver function tests measuring serum ALT (alanine transferase) and ALT (aspartate aminotransferase). These test results can far exceed normal baseline values and do not correlate with liver damage. This presents a very confusing picture for clinicians who closely monitor liver function tests as a sign of toxicity to ARVs or TB medications. It may be unclear if a patient with high ALT or AST is developing serious liver toxicity with damage, or if these high values are merely the fluctuating pattern of HCV disease. China’s Free ART National Guideline does address the special situations of HCV co-infection when considering antitretrovirals, but many clinicians remain nervous about treating patients with ARVs when liver function tests are very elevated. Mentoring by experienced physicians over the course of seeing a number of these HCV cases permits the clinician to gain a measure of confidence in their judgment of juggling ARV and TB therapies.
Complexity of Antiretroviral Drug Regimens for Patients with Co-Infections
The drugs most commonly used for first line combination ARV therapy in many countries are known to have associated risks for liver damage, most notably nevirapine, stavudine (d4T) and didanosine (ddI). This influences the choice of ARV regimen in patients with TB/HIV. In China, for example, the ART national guidelines direct that efavirenz should be substituted for nevirapine in patients being treated for TB in order to lessen their risk of liver damage. However, efavirenz is more expensive and not always available.
In addition to the risk of liver toxicity with certain TB therapies, some TB medications also alter the metabolism of certain antiretrovirals. This situation may require adjustment in the doses of ARVs given to patients, and is an important point when training clinicians in ARV management. When patients need concurrent treatment for HIV and TB, both antiretroviral and TB regimens need to be chosen carefully and tailored to minimize drug interactions and toxicities. For example, in China the treatment regimen for TB includes a six-month course of four medications. For patients on ARVs, rifampicin is prescribed instead of rifampin to reduce drug interactions. Another drug, Isoniazid, has well known risks for liver toxicity but it is a cornerstone in the treatment of TB and continues to be used with careful monitoring. Both the effects of the underlying co-infections and the complications of therapy mean that attentive clinical and laboratory monitoring is important to ensure that patients are safely treated. The cost of treating patients with these overlapping conditions is commonly higher due to this closer monitoring.
Altering the Training Approach
The challenges in the clinical care of these three co-infections places special demands on training of health professionals. The complexity of managing difficult cases means that standard protocols and straightforward algorithms cannot always be applied. Instead, individual clinical judgment needs to be supported through mentoring, referral and consultation support until clinicians become comfortable in knowing when to start, stop or change therapies.
Training needs to also take into account the way in which systems of care are organized. For example, TB control programs are frequently operated as distinct programs within the ministry of health because of their public health importance and history. Now with the closely linked epidemics of HIV and TB, close coordination in case finding and effective referral mechanisms between medical care facilities and TB control programs are more important than ever. Cross-training approaches that bring HIV care providers and TB clinic providers together can help to build a good base for effective referral or shared follow-up of patients with TB/HIV co-infection.
There is abundant evidence that individuals with complex medical needs of HIV, TB and HCV co-infections can be successfully treated and remain in good health for years. However, due to the nuances of managing drug interactions and toxicities against the backdrop of underlying liver disease, simple standardized guidelines for care do not fit in many cases. Training approaches that add clinical mentoring to build knowledge and experience among clinicians may appear more difficult at the start, but result in better decision-making and patient outcomes. This clinical mentoring approach is especially important in those areas where expanding epidemics related to injection drug use increase the numbers of patients diagnosed with all three conditions.
For further information, contact dvonz@comcast.net
This article was originally published in Global AIDSLink September/October 2006 by the Global Health Council.