Surviving with HIV in the HAART era: emerging challenges.

Even though highly active antiretroviral therapy (HAART) has helped many keep HIV disease at bay, HIV-infected persons must not become complacent by equating good health with undetectable viral loads and CD4 T cell counts above 200 cells/[mm.sup.3]. It has become increasingly, if not painfully, apparent that other risks exist with the potential of causing serious complications or even death. If only all that was required was to achieve and maintain an undetectable viral load.

Perhaps most ironic for HIV-infected people living in the HAART era is the risk for disorders like insulin resistance and elevated cholesterol and triglyceride levels, which commonly threaten the general population. Aside from cardiovascular risk, incidence of liver failure is increasing as a cause of death in HIV-infected patients. Also, HIV-related cancers continue to threaten survival. This changing HIV landscape may be a result of the use of HAART, extended survival time or some combination of factors.

Research is desperately needed to determine what risks, if any, metabolic abnormalities pose for HIV-infected individuals. Are these risks more, less or equally likely to produce disease compared to the general population? Likewise, can HIV-related cancers be treated in the same ways as cancers in uninfected individuals, considering that HAART is a form of chemotherapy itself?

Before HAART, progression of HIV infection to AIDS was inevitable. Opportunistic infections almost always caused death. But HAART has affected this natural progression in ways that researchers still scarcely understand. What is known is that HIV-infected patients are faced with new threats and must be more conscious than ever of health risks and important lifestyle decisions in order to survive.

Looking at the liver. The liver can suffer direct damage as the result of HAART. In addition, co-infection with hepatitis is believed to be a factor in the increased incidence of liver failure. However, even when infection with hepatitis occurs and resolves prior to HIV infection, patients may be at increased risk of liver complications.

Many anti-HIV drugs have been shown to induce liver function abnormalities. Nucleoside reverse transcriptase inhibitors (NRTIs) in particular have been associated with lactic acidosis (elevated levels of lactic acid in the blood) and hepatic steatosis (fatty liver). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) can cause elevated liver enzymes, a sign of liver stress and potential damage. Prolonged stress on the liver can result in acute liver disease. However, research has not established what role HAART might play in the increasing number of deaths caused by liver failure.

An important precaution is to monitor liver enzyme levels when blood work is done. Usually HIV-treating physicians have such tests performed regularly. If elevated enzymes are detected and attributable to anti-HIV drug side effects, the patient may withdraw from drug for a time and later restart. This strategy is often successful. Sometimes patients may need to change their regimen, a situation particularly critical for those co-infected with hepatitis.

What else can HIV-infected patients do? Vaccination against hepatitis B is an important preventive step to help avoid potential liver damage. A simple blood test will reveal the presence of hepatitis antibodies. If antibody negative, an HIV-infected individual should be vaccinated against hepatitis B, which can be spread sexually. There is no vaccine for hepatitis C, commonly spread through contaminated blood, intravenous needle sharing and, to a much lesser extent, through sex. Avoiding other stresses on the liver like heavy alcohol use may also be beneficial.

Heart to HAART. Elevated triglyceride and cholesterol levels are common side effects associated with HAART, particularly protease inhibitors (PIs). The PIs are also strongly suspected of playing a role in the fat changes experienced by some patients on HAART, although the mechanism for this has yet to be identified. Many HIV-infected patients have experienced fasting triglyceride levels in the hundreds, meaning that if a fatty meal is ingested those numbers could rise into the thousands. Such levels are considered dangerously high because they are associated with increased risk of pancreatitis (inflammation of the pancreas) and atherosclerosis (clogging of the arteries). This risk is magnified in the presence of other factors like hypertension, smoking, obesity, diabetes, etc.

Thus, reducing risk factors may be an important strategy for patients on HAART. Usual interventions in the uninfected population include regular exercise and a diet low in fat. However, some physicians opt to lower blood lipid levels using medication, especially in situations where multiple factors place the patient at high risk for cardiovascular disease. This approach must be taken with caution since PIs interact with some lipid-lowering drugs known as statins, causing severe and potentially fatal toxicity.

Insulin resistance is another side effect associated with PI use during HAART. This condition can lead to diabetes mellitus, which is linked to cardiovascular disease as well. So far, the prevalence of diabetes among HIV-infected persons on HAART has not increased as compared to the uninfected population.

The clinical significance of such metabolic events in HIV-infected patients on HAART is still being determined. Since widespread use of HAART is scarcely 5 years old, another 5 years may be required to observe any effects on the survival of these patients. In the meantime, patients should consider reducing risk factors like smoking and obesity, which can lead to heart attacks and strokes.

Cancer: another price of survival? Even in the days before HAART, certain cancers were prevalent in the HIV/AIDS population, most notably Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL). The development of these cancers, rare in the general population, is associated with immune suppression. For example, these same cancers are usually seen in transplant patients taking immunosuppressive drugs. Of note, these cancers are virus-associated. Epstein-Barr virus (a type of herpes virus) is associated with the development of NHL and human herpesvirus 8 (HHV-8) is associated with KS. In addition, human papillomavirus (HPV) has been implicated in the development of cervical and anal cancers. (HPV is also responsible for the development of oral warts; see review on page 19). At present, the incidence of KS and primary brain lymphoma has declined markedly, while that of NHL and other cancers (cervical, anal, lung, etc.) is steadily increasing in the HIV-infected population.

HAART results in an improved chemotherapy response and overall survival in patients with AIDS-related lymphoma. But researchers caution that until now HAART has proven incompletely effective in rebuilding the immune system, which may account for the increasing incidence of certain types of cancer like NHL. (See clinical review of NHL.)

It is also important to recognize any potential toxicity that might occur when using cancer chemotherapy with HAART. Research indicates that in most cases, combining the therapies is safe. However, some interactions are possible; for example, zidovudine (Retrovir) should be avoided in patients receiving chemotherapy for cancer since both cause bone marrow toxicity. Also, some protease inhibitors may produce toxicity when combined with infusional cancer chemotherapy regimens. One study implicated saquinavir (Fortovase) with increased likelihood of developing grade 3 or 4 mucositis (inflammation of the mouth).

Patients and physicians must be aware of the risks for developing certain kinds of cancer. Preventive screening, such as the Pap test, has been proven to lower the incidence of cervical cancer in women. Likewise, an increasing number of HIV-treating physicians are beginning to use the Pap test to screen for precancerous lesions that can lead to anal squamous cell cancer in both men and women. With cancers such as these, early intervention is key to survival. Other cancers are more difficult to identify without specific tests, but HIV-infected patients should regularly inspect themselves for any unusual bumps or lesions and report anything suspicious to their physicians.

Summary. It is clear that metabolic disorders and cancers will continue to be important risks for HIV-infected individuals, especially in the long term. Patients must be aware of new potential risks and, when possible, take preventive measures. In this context, HIV becomes one major aspect of a patient's health, but not the entire focus. By concentrating on the changing aspects of HIV disease, researchers and physicians are keeping pace with a disease that always reveals new information not only about itself, but also on how the immune system functions.