There have been significant decreases in the incidence rates of opportunistic infections in developed countries since HAART (highly active antiretroviral therapy) use became widespread. This decrease has led both HIV clinicians and patients to question the necessity of pharmaceutical preventative measures (also known as prophylaxis or prophylactic treatments) against opportunistic infections. At the September 1999 Community Forum, Drs. Brian Boyle and Fred Valentine discussed the role of immune reconstitution in fighting opportunistic infections and made recommendations regarding prophylaxis for these infections.

An Introduction to Opportunistic Infections and Common Prophylactic Treatments

Pneumocystis carinii Pneumonia (PCP) is a specific type of pneumonia- an infection of the lung. Most people are infected with the organism that causes PCP early in life, but the immune system keeps the infection under control. When HIV weakens the immune system, PCP can develop. Although PCP can be prevented and treated, it is one of the leading causes of illness and death in people with HIV. Early signs of PCP are difficulty in breathing, fever, and coughing.

The most common prophylactic treatment for PCP is trimethoprim/sulfmethoxzole (also known as TMP/SMX or Bactrim a Sulfa drug). Other prophylactic methods include dapsone, aerosolized pentamadine and atovaquone. The most commonly observed side effect of Bactrim is allergic reaction, and other side effects can include minor fevers, nausea, low white blood cells, low platelets, and liver irritation. Desensitization, a process in which Bactrim treatment is initiated at a low dose and then increased gradually, can sometimes prevent allergic reactions. Dapsone can cause fever, rash, nausea, liver problems, back, leg, or stomach pain, bluish color change in lips and fingernails, breathing problems, and low energy levels. Pentamidine can cause kidney and liver problems, low blood sugar, high blood sugar, low white blood cell counts, low blood pressure, and inflammation of the pancreas.

Mycobacterium Avium Complex (MAC), is an infection related to tuberculosis. MAC usually affects the intestines and inner organs, and its symptoms can include weight loss, fevers, chills, night sweats, swollen glands, abdominal pains, diarrhea, and overall weakness.

Rifabutin (also known as Mycobutin), is an effective prophylactic treatment for MAC. Clarithromycin (Biaxin) and azithromycin are also approved for the prevention of MAC. A recent AIDS Clinical Trials Group (ACTG) study of azithromycin for MAC prophylaxis showed no benefit to azithromycin prophylaxis for people whose CD4+cell (T-cell) count had risen to over 100 while on HAART. The treatment is effective for individuals with lower CD4+ cell counts, however. The most serious side effects of rifabutin are low white blood cell counts and elevated liver enzymes. Side effects of clarithromycin can include diarrhea, nausea, and abnormal or metallic taste. Side effects of azithromycin include mild gastrointestinal symptoms such as nausea and diarrhea, dizziness, sensitivity to sunlight, and rare cases of hearing loss.

Toxoplasmosis is an infection caused by a parasite called toxoplasma gondii. Common sources of infection are cats, birds, other animals, and undercooked meat. The parasite can also be found in soil contaminated by animal feces. Toxoplasmosis most often affects the brain, and its symptoms include severe headaches, weakness on one side of the body, fever, seizures, problems with seeing and difficulty speaking and walking.

Bactrim can be used to prevent toxoplasmosis, as can the combination of dapsone and pyrimethamine. The main side effects from Bactrim and dapsone are listed above. Pyrimethamine can cause bone marrow suppression, rash, nausea, and vomiting.

Cytomegalovirus (CMV) is a member of the herpes virus family. The most common illness caused by CMV in people with AIDS is CMV retinitis, an infection of the eye that can lead to blindness. Left untreated, CMV can spread throughout the body. The signs of CMV retinitis are vision problems or blind spots.

Two recent clinical studies (Roche study #1654 and CPCRA study #023) examined the use of oral ganciclovir for CMV prophylaxis. Both studies showed no difference in survival between groups receiving oral ganciclovir or placebo. The Roche study showed a lower incidence rate of CMV disease in the group receiving oral ganciclovir than in the placebo group (24% vs. 12% of subjects developed retinitis after one year).

The indication of oral ganciclovir as a prophylactic method has become increasingly accepted. It is not widely used, however, because of high cost, the possibility of developing resistance, and the fact that three-quarters of patients would not benefit from prophylaxis because the incidence rate of CMV retinitis is fairly low. A5030, an upcoming ACTG study, will screen subjects at high risk for CMV disease. Subjects with CMV will receive either oral valganciclovir, an improved form of oral ganciclovir, or placebo.

Clinical Studies of Prophylaxis Discontinuation

CD4+ count increases and undetectable viral loads have become more common in the era of HAART, and researchers have begun to investigate the effects of discontinuing prophylactic treatment in individuals who have been successfully treated with HAART.

At the International AIDS Conference in Geneva in 1998, Ravaux and colleagues presented a retrospective study of 40 subjects who discontinued Bactrim treatment. All of the subjects had CD4+ cell counts greater than 300 and viral load measurements less than 500 copies. 12 of the subjects restarted prophylaxis because their viral loads became detectable and they were again susceptible to developing opportunistic infections. There were no cases of PCP or toxoplasmosis in the other 28 subjects. The researchers suggested that it is reasonable to discontinue PCP/toxo prophylaxis as long as patients are monitored carefully and therapy is reinitiated if viral load increases or CD4+ count decreases.

A study by Dworkin and colleagues presented at the 1999 Conference of Retroviruses and Opportunistic Infections examined PCP incidence rates among three groups - Group 1, who at one time had fewer than 200 CD4+ cells, but whose counts had risen to greater that 200 while on HAART, Group 2, who had never had a count less than 200, and Group 3, composed of subjects from Groups I and 2 whose counts dropped below 200 while on the study. The results showed no significant difference in PCP incidence rates between members of Groups 1 and 2. There was, however, a significant difference in the incidence rates between members of Group 3 and the two other groups. The researchers concluded that the incidence rate of PCP is low in people with more than 200 CD4+ cells, and that prophylaxis may not be warranted. The more interesting implication of the study, however, is that CD4+ cells gained as a result of HAART treatment may have the same effectiveness in fighting disease as CD4+ cells that were originally present.

A study presented by Tural and colleagues at the International AIDS Conference in Geneva in 1998 explored the effects of discontinuing secondary prophylaxis for CMV retinitis. 16 subjects with a previous CMV retinitis diagnosis started HAART treatment, and 7 of the 16 stopped their secondary CMV prophylaxis when their CD4+ counts were greater than 150 cells and their viral loads reached undetectable. There were no incidences of CMV retinitis in the group during a 14-month follow-up period. The results indicate that in subjects with healed CMV retinitis and increased immunologic function due to HAART, withdrawal of CMV prophylaxis may not lead to further incidences of CMV retinitis.

Guidelines for Prophylaxis Discontinuation

Dr. Boyle presented the guidelines for stopping prophylaxis that were published in August 1999 by the Morbidity and Mortality Weekly Report (MMWR).

Note: Primary prophylaxis refers to treatment for people who have not had the OI. Secondary prophylaxis refers to treatment for people who have had the OI.

• CD4+ cell count greater than 200 for 3 - 6 months

• No criteria recommended for stopping

• CD4+ cell count greater than 100 for 3 - 6 months
• Undetectable viral load with durable suppression

No criteria recommended for stopping

• Not applicable

• CD4+ cell count greater than 150 for 3 - 6 months
• Undetectable viral load with durable suppression
• Non-sight-threatening lesion
• Adequate vision in contralaterial eye
• Regular ophthalmic exams

• CD4+ cell count <50 - 100 cells

Dr. Boyle emphasized that strengthening the immune system with HAART therapy is the most effective approach to preventing OIs. He also stated that prophylaxis against individual OIs can provide survival benefits, and that individuals who have failed their antiretroviral regimens should continue prophylactic measures, as it is their best defense against developing OIs. Dr. Boyle recommended having a CMV viral load test performed to ensure that CMV is not present in the plasma before discontinuing CMV prophylaxis.

The impact on quality of life must be considered when determining whether or not to use prophylactic measures. If an individual has a high pill burden and has a stable undetectable viral load with high CD4+ cells, the added inconvenience of prophylactic measures may not be necessary, especially since there are toxicity and drug interaction risks associated with all prophylactic measures.

Immune Function and Opportunistic Infections

Immunologic reconstitution has been observed in many individuals with previously compromised immune function as a result of HAART therapy. These individuals have an increased capability for preventing the development of opportunistic infections.

It is important to understand the basics of immune function and the role of CD4+ cells in fighting disease. When a virus or other antigen enters the body, it is recognized as foreign by immune cells, and the body begins its response to the foreign material by reproducing CD4+ cells at a high rate. This reproduction is called the lymphocyte proliferative response (LPR), and it occurs in a Clonal manner, so that all of the new cells produced are able to recognize the same antigen. In a person with normal immune function, strong LPR is an important component of the ability to fight infection. In HIV-infected people, treatment with HAART can increase the number of CD4+ cells, but it does not necessarily improve the LPR against disease-causing antigens.

Clinical Studies of Immune Response to OI Antigens

The increase in CD4+ cells achieved with HAART can lead to an increased LPR to certain disease-causing microorganisms, such as those responsible for PCP, MAC, and CMV disease. A study presented by Schrier and colleagues at the 1999 Conference of Retroviruses and Opportunistic Infections examined CD4+ function in patients who had less than 100 CD4+ cells before starting HAART and who had developed CMV retinitis. At the beginning of the study, the patients' CD4+ function was poor, with few responses to disease-causing agents, but after 6 months, about 70% of subjects had CD4+ cells that responded to CMV and candida, over 50% had CD4+ cells that responded to MAC antigens, and 20-30% had CD4+ cells that responded to toxoplasma and herpes virus. The CD4+ cells were also presented with HIV antigen, and 40 % of the subjects' CD4+ cells responded to at least one HIV antigen. The presence of active CD4+ cells translates into clinical benefit to patients.

There are interesting individual case studies in which an increase in CD4+ cells has not necessarily led to protection against opportunistic infections. Dr. Valentine described a patient whose CD4+ cell count rose from approximately 100 to 400 cells, and who then experienced an unexpected case of PCP. It was later determined that the subject's immune system was unable to generate an LPR to the PCP antigen. CD4+ cells are highly specific, and there are very few that recognize each individual antigen. If an individual is missing an antigen-specific CD4+ cell, his or her immune system will be unable to launch an immune response to that antigen.

For further details about restoration of immune function, please see the March 1999 Community Forum summary.

Questions and Answers

Q: Can I develop resistance to Bactrim? Is it OK to start and stop Bactrim therapy?

A: While resistance will not develop, it is not a great idea to stop and start Bactrim, especially if your CD4+ cells are low, because the medication will not be as effective in preventing PCP as if it were taken consistently.

Q: Is there general access to the CMV viral load testing that Dr. Boyle described?

A: This test is not currently available to the general public, however, it is in development for wide-scale use. If clinical studies show that there is benefit (with respect to treatment decisions) to knowing whether CMV is present in the plasma, interest in test development will certainly increase.