Why Do People Taking Antiretroviral Medications Seem Sicker Than People Not Taking ARVs? Do ARVs Make You Sicker?

People often write in saying "HIV positive people who are taking ARVs seem to be sicker than HIV positive people who are not taking ARVs. Therefore, I think that HIV is not the cause of AIDS, and/or that ARVs make you sicker and are actually causing the symptoms that doctors say are symptoms of AIDS." We once received an email from a person who had counted their HIV positive friends who were on ARVs and not on ARVs and compared their health in detail over time, concluding that their "scientific study" of the two groups had shown that people on ARVs are sicker than people who are not taking ARVs, and that therefore ARVs are harmful.

People who draw this conclusion are making a basic but understandable mistake: they are comparing apples and oranges. In standard medical practice today, ARVs are usually prescribed in the later stages of HIV infection (typically, to people whose CD4 count has fallen below 350 and/or have developed an opportunistic infection indicating that their immune system has grown weaker). Therefore, HIV positive people who need to be prescribed ARVs are by definition sicker (further along in the course of their HIV infection, needing help from ARVs to stay healthy) than HIV positive people who do not need to be prescribed ARVs.

Therefore, if you want to determine whether ARVs are helpful or harmful for people who are HIV positive, you can't compare the health of HIV positive people who are on ARVs with the health of HIV positive people who aren't on ARVs because that would be comparing apples and oranges. "People not taking ARVs" are not a matched control group for "people taking ARVs" because the two groups are have a basic difference: "people taking ARVs" are further along in the course of their HIV infection than "people not taking ARVs."

It may be easier to see the mistake people are making if you think about two other conditions people are more familiar with: coronary artery disease and diabetes.

Example: Coronary Artery Disease

Having high cholesterol is a risk factor for developing coronary artery disease and having heart attacks. In the later stages of coronary artery disease, fatty plaques build up within the arteries that supply blood to the heart. This increases the risk of a clot blocking one of those arteries, causing a heart attack and possibly leading to death.

People who have advanced, later-stage coronoary artery disease may be given a heart bypass operation in which veins from the leg are surgically grafted on to the heart to act as "backup" arteries that carry blood around the arteries that are nearly blocked. Having a bypass operation may reduce your risk of a heart attack and death if you have advanced coronary artery disease.

If you were trying to understand whether bypass surgery is helpful or harmful, you might look at all your friends who have high cholesterol and compare "people with high cholesterol who had bypass surgery" with "people with high cholesterol who didn't have bypass surgery." Those who underwent bypass surgery would have a fair number of heart attacks and deaths. Those who don't have bypass surgery would have fewer heart attacks and deaths. Does it follow therefore that bypass surgery causes heart attacks and deaths? This is precisely the (incorrect) conclusion you'd reach if you took this approach.

But no, that's not what it means. It means that if people have high cholesterol but no coronary artery blockage, they aren't prescribed a bypass. If people have high cholesterol and later stage coronary artery disease including significant blockage of their coronary arteries, bypass surgery may reduce the risk of fatal heart attacks, but the "later stage" group with blocked coronary arteries will still have a higher death rate than the "early stage" group with no coronary artery blockage because they were sicker to begin with. The same is true for HIV, ARVs, and clinical AIDS and the death rate from it.

Example: Type 2 Diabetes

Having low blood sugar can be a symptom of type 2 diabetes, which can lead to problems like diabetic shock, blindness, leg infections, and death. People with mild type 2 diabetes may be able to satisfactorily control it through diet and exercise. People with more serious, later-stage type 2 diabetes cannot control it through diet and exercise alone and may require insulin injections.

If you were trying to understand whether insulin injections are helpful or harmful for low blood sugar due to type 2 diabetes, you might look at all your friends who have ow blood sugar due to type 2 diabetes and compare "people with low blood sugar due to type 2 diabetes who take insulin injections" with "people with low blood sugar due to type 2 diabetes who don't take insulin injections." Those who take insulin injections would have some number of deaths. Those who don't take insulin injections would have fewer deaths. Does it follow therefore that taking insulin injections as prescribed by a doctor increases your risk of death? This is precisely the (incorrect) conclusion you'd reach if you took this approach.

But no, that's not what it means. It means that if people have mild type 2 diabetes that's controllable via diet and exercise, they aren't prescribed insulin injections. If people have serious type 2 diabetes that can't be controlled through diet and exercise, insulin injections may reduce the risk of death, but the "later stage" group with serious type 2 diabetes will still have a higher death rate than the "early stage" group with no mild diabetes because they were sicker to begin with. The same is true for HIV, ARVs, and clinical AIDS and the death rate from it.

Valid and Invalid Ways of Studying the Effectiveness of ARVs for HIV, Bypass Surgery for Coronary Artery Disease, and Insulin for Type 2 Diabetes

Here is a table summing up valid and invalid ways of studying the effectiveness of ARVs, bypass surgery, and insulin and the correct or incorrect conclusions you'll reach if you apply them.

Disease
HIV Disease
Coronary Artery Disease
Type 2 Diabetes
Underlying Cause of Disease
being infected with HIV (HIV positive)
body biochemistry is leading to a high level of "bad" LDL cholesterol in the bloodstream
body develops insulin resistence, so sugar builds up to high levels in the bloodstream
"Early Stage" Group
people who are HIV positive but have a CD4 count greater than 350 and who have not experienced an opportunistic infection
people who have a tendency towards high "bad" LDL cholesterol but can keep it down through diet, exercise, and/or the use of statins like Lipitor
people tend to have high blood sugar levels but can control it through diet and exercise
"Late Stage" Group
people who are HIV positive but have a CD4 count below 350 and/or have experienced an opportunistic infection people who have developed plaques that almost completely obstruct the flow of blood through the coronary arteries to the heart
people whose blood sugar levels cannot adequately be controlled through diet and exercise
Partial List of Symptoms Possibly Experienced by "Late Stage" Group
CD4 count below 350, progression to clinical AIDS (diagnosed when an HIV positive patient has a CD4 count under 200 or experiences an opportunistic infection), higher risk of opportunistic infections, higher risk of death
chest pain during exercise, higher risk of heart attack, higher risk of death
higher risk of diabetic shock,  blindness, infections in the legs, and death
Treatment That May  Be Prescribed to "Late Stage" Group
use of antiretroviral medications (ARVs)
bypass surgery
insulin injections
Scientific Question
Does the use of ARVs for people with "Late Stage" HIV disease increase the CD4 count, reduce opportunistic infections, and reduce the death rate?
Does bypass surgery for people with "Late Stage" coronary artery disease reduce the risk of heart attacks reduce the death rate? Do insulin injections for people with "Late Stage" diabetes reduce the risk of diabetic shock, blindness, leg infections, and death?
Invalid Study Methodology for Resolving the Scientific Question
"Let's take all the HIV positive people and compare the death rate of people who are on ARVs with the death rate of people who aren't on ARVs."
"Let's take all the people with high "bad" LDL cholesterol and compare the death rate of people who have bypass surgery with the death rate of people who don't have bypass surgery." "Let's take all the people with high blood sugar levels due to type 2 diabetes and compare the death rate of people who take insulin injections with the death rate of people who don't take insulin injections."
Proposed "Test Group" in Invalid Methodology
HIV positive people who have been prescribed and are taking ARVs
people with high "bad" LDL cholesterol who meet the criteria for and undergo heart bypass surgery
people with high blood sugar levels due to type 2 diabetes who have been prescribed and are taking insulin injections
Proposed "Control Group" in Invalid Methodology
HIV positive people who do not meet the criteria to be prescribed ARVs
people with high "bad" LDL cholesterol who do not meet the criteria for bypass surgery people with high blood sugar levels due to type 2 diabetes who do not meet the criteria to be prescribed insulin injections
Test Criterion
death rate
death rate death rate
Invalid Conclusion Reached by Invalid Study Methodology
"HIV positive people who are on ARVs have a higher death rate than HIV positive people not taking ARVs, therefore ARVs must be harmful." (This is wrong.)
"People with high "bad" LDL cholesterol who have bypass surgery have a higher death rate than people with high "bad" LDL cholesterol who don't have bypass surgery, therefore bypass surgery must be harmful." (This is wrong.) "People with high blood sugar levels due to type 2 diabetes who take insulin injections have a higher death rate than people with high blood sugar levels due to type 2 diabetes who don't take insulin injections, therefore insulin injections must be harmful." (This is wrong.)
Fatal Flaw of Invalid Study Methodology
Error in test/control group definition in study design. "Test Group" and "Control Group" are not equivalent. "Test Group" members have CD4 counts under 350 and/or have experienced an opportunistic infection. "Control Group" members have CD4 counts above 350 and have not experienced an opportunistic infection. Therefore, "Test Group" members are by definition sicker (further progressed in HIV disease) than "Control Group" members and are automatically expected to have a higher death rate.
Error in test/control group definition in study design. "Test Group" and "Control Group" are not equivalent. "Test Group" members have advanced coronary artery disease with significant blockage of their coronary arteries. "Control Group" members have high "bad" LDL cholesterol but mild or no coronary artery blockage. Therefore, "Test Group" members are by definition sicker (further progressed in coronary artery disease) than "Control Group" members and are automatically expected to have a higher death rate. Error in test/control group definition in study design. "Test Group" and "Control Group" are not equivalent. "Test Group" members have serious type 2 diabetes that cannot be controlled with diet and exercise. "Control Group" members have mild type 2 diabetes that can be satisfactorily controlled through diet and exercise. Therefore, "Test Group" members are by definition sicker than "Control Group" members and are automatically expected to have a higher death rate.
Valid Study Methodology for Resolving the Scientific Question (Simplified for Illustrative Purposes -- see note below)
"Let's take the HIV positive people who meet the criteria for prescribing ARVs, divide them into two groups, give one group ARVs and one group a placebo, and compare the death rate of the two groups." (see note below)
"Let's take the people with high "bad" LDL cholesterol who meet the criteria for bypass surgery, divide them into two groups, give one group bypass surgery and one group a placebo pill, and compare the death rate of the two groups." (see note below) "Let's take the people with high blood sugar levels due to type 2 diabetes who meet the criteria for prescribing insulin injections, divide them into two groups, give one group insulin injections and one group a placebo pill, and compare the death rate of the two groups." (see note below)
"Test Group" in Valid Methodology HIV positive people who meet the criteria for prescribing ARVs and are given ARVs
people with high "bad" LDL cholesterol who meet the criteria for bypass surgery and are given bypass surgery
people with high blood sugar levels due to type 2 diabetes who meet the criteria for insulin injections and are given insulin injections
"Control Group" in Valid Methodology HIV positive people who meet the criteria for prescribing ARVs and are given a placebo
people with high "bad" LDL cholesterol who meet the criteria for bypass surgery and are given a placebo pill
people with high blood sugar levels due to type 2 diabetes who meet the criteria for insulin injections and are given a placebo pill
Valid Conclusion Reached by Valid Study Methodology For HIV positive people who meet the criteria for prescribing ARVs, those who take ARVs have a lower death rate than matched control subjects who don't take ARVs. Therefore ARVs are effective for the treatment of "Late Stage" HIV disease.
For people with high "bad" LDL cholesterol who meet the criteria for bypass surgery, those who undergo bypass surgery have a lower death rate than matched control subjects who don't undergo bypass surgery. Therefore bypass surgery is effective for the treatment of "Late Stage" coronary artery disease. For people with high blood sugar levels due to type 2 diabetes who meet the criteria for insulin injections, those who take insulin injections have a lower death rate than matched control subjects who don't take insulin injections. Therefore insulin injections are effective for the treatment of "Late Stage" type 2 diabetes.

Simplifications in Above Explanations

This page is by no means intended to give a complete explanation of the causes, course, and/or treatment of HIV/AIDS, coronary artery disease, and type 2 diabetes. Coronary artery disease and diabetes in particular can have multiple contributing factors. This page presents a simplified explanation of HIV, coronary artery disease, and type 2 diabetes that is for illustrative purposes only.

The above "scientific study designs" are simplified for illustrative purposes.  Real-world clinical studies would have to be more complex and would take more issues into consideration:

Controlled Scientific Studies Have Proven That ARVs Are Effective for Treating HIV

There's no remaining question, scientifically speaking, about whether or not ARVs are helpful for people whose HIV infection has progressed to the point that ARVs are typically prescribed (such as CD4 count of 350 or less, or presenting an opportunistic infection that's indicative of a weakened immune system). Too many controlled clinical trials have been done, and the results have consistently shown that ARVs reduce the death rate, opportunistic infection rate, and speed of progression to clinical AIDS for those who meet the diagnostic criteria for prescribing them.

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