Perspectives on When To Begin Therapy
     Editorial from Jules Levin

This question is receiving increased attention. Many studies have been presented lately. Let me briefly tell you what these studies have said & the limitations of these studies. Several studies show you can increase improve cd4s & viral load equally whether you start HAART at 200-350 or at above 350. Several other studies have shown the opposite-- that when starting therapy early, cd4s & viral load improve more & the response is more durable (if patient is adherent). These studies are mostly all relatively short term in their follow-up. In other words, patients have been followed for only 1-3 years. If you are following someone for only 3 years that may be too short to see a difference in HIV progression between starting therapy at 250 cd4s vs starting at 400 cd4s. Most doctors & researchers agree that biologically speaking HIV treatment should be started early. From a medical & scientific point of view, therapy for this disease should be started early, once you start HAART the immune system decline from HIV stops. But, there are so many difficulties once you start therapy. The side effects, toxicities, difficulties in adherence, etc. are the reasons considered for deferring therapy.

The Federal Treatment Guidelines for Adults recently changed. Previously, they recommended considering therapy when cd4s were 500 or viral load 20,000 by PCR. The new Guidelines recommend therapy at 350 cd4s or viral load of 55,000 copies/ml by PCR. The Guidelines also say discretion as to when to begin is left to doctor/patient.

I'm not a fan of the Guidelines. There is no clear answer on when to begin therapy and conducting one large study to answer this is very difficult and I think would not yield the answers to our questions. Deciding when to begin therapy is a personal & individual decision. Every patient has an individual situation, which is different from everyone else. Lifestyles, eating habits, preferences about therapy (which side effects are tolerable to them, etc), CD4s, viral load are all different between individuals. Each individual has their own personal concerns, which will differ from other's concerns. A person should weigh in deciding when to begin therapy the potential risks & benefits of starting or deferring therapy. Below is a discussion of many of the things to consider. This list of benefits & risks may not be exhaustive.

Why should a person start therapy early (when cd4s are 350-500)? After starting therapy people tend to develop certain adverse effects, side effects, & toxicities. But there are potential benefits to beginning therapy early, when CD4s are over 350 or at 500. The risks and benefits should be carefully weighed by the patient, with their doctor before deciding when to begin therapy. HIV-related CNS disorders may be more likely to occur as viral load gets higher. HIV and certain HIV medications can lead to peripheral neuropathy. To be clear, without ever taking any HIV medications, just having HIV may lead to peripheral neuropathy and other HIV-related CNS disorders. We know that shortly after a person becomes HIV-iinfected HIV enters the Central Nervous System. Data has shown that viral load over 10,000 increases risk for peripheral neuropathy by 25% over a 10-year period. Lower CD4s can also increase this risk. HIV by itself can also lead to neuropathy. In general, when HAART is started the immune system stops the decline caused by HIV: CD4s increase, the cd4/cd8 ratio improves, etc. Deferring therapy & letting cd4 count decline permits continual decline in the immune system. We don't know what cd4 count is the cut-off for increased risks. Over the course of many years cancers may be more likely to develop if CD4s go to low before starting therapy. We don't have data proving this but this is a concern. It could take many more years before we see cancers starting to pop up. Allowing viral load to replicate unchecked permits a patient's virus to mutate & become genetically diverse. This may have the effect of reducing the response to therapy. Several studies show that individuals who start therapy when cd4s are 350-500 respond better to therapy which in theory (if person remains adherent) should lead to more durability in response.

Why should a person defer therapy & til when when cd4s are >350 or 200)? After starting therapy certain side effects & toxicities may occur. Some people may prefer to delay therapy to defer experiencing them. After starting therapy you risk developing lipodystrophy. A significant percentage (estimated to be 20-50%) of patients taking HAART develop what's generally called "lipodystrophy". This syndrome includes body changes: fat loss in the arms, face, buttocks, hip area, legs; fat accumulation in breasts for women & much less likely in men, stomach, fat pads developing on back of neck called "buffalo hump). Protease inhibitors can lead to elevated cholesterol, triglycerides and less likely elevated sugar & diabetes. Elevated liver enzymes can occur after starting therapy. For the person with hepatitis B or C, these elevations may be higher & people are concerned if elevations are high. We don't know how risky it is for people with hepatitis & HIV to experience high elevations in liver enzymes (ALT), but we are concerned about it. Elevated liver enzymes create inflammation in the liver. The question we don't have an answer to --does this inflammation lead to increased fibrosis & liver damage harmful to HCV progression. For some individuals, it may be preferable to start HCV therapy before HIV therapy. A number of studies show that increasing cd4s to 300 or more after starting HAART appears to protect people from getting the major opportunistic infections they were in risk of getting when their cd4s were <200 or <100. Some doctors feel that a patient has the best chance of achieving the highest cd4 increases when starting therapy earlier. They feel deferring therapy until cd4s are lower risks that cd4 increases may not be as large. However, a couple of studies suggest this may not be true. These studies suggest cd4 increases may be the same whether you start at 250 or 400 cd4s.

Adherence & Lifestyle Changes. Once a person begins therapy they need to adhere closely to a strict schedule of taking the medications. This requires taking pills at least twice daily, although there are a few once-a-day regimens. There are several twice daily regimens that have very minimal numbers of pills but you have to speak to your doctor about whether they are appropriate for your individual situation. Still, a patient will HAVE TO remember to take the pills on time every day. Certain pills must be taken with food and others don't have to be taken with food. But the patient is required to remember these details & to follow these requirements. This restricts your lifestyle. Since adherence is difficult and many people are not able to adhere, they can develop resistance to the HIV drugs. Some people think this limits future treatment options. But many doctors do not feel that way since there are many options available now and a number of additional treatments are in development.