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Cytomegalovirus (CMV) is the most common cause of sight-threateninginfections in and one of the most common causes of death among peoplewith HIV. Therapies are available to reduce the occurrence of CMV- disease. There have been some significant advances in CMV treatmentover the past several years. Also, CMV disease has responded surpris-ingly well to the use of HAART (Highly Active Antiretroviral Therapy).
CMV is a member of the herpes family of viruses and is primarily a Encephalitis. CMV can also infect the brain and the nervous system sexually transmitted disease, but it can also be transmitted from in the form of inflammation of the brain (encephalitis) and inflam- mother-to-child, through blood transfusions, by close personal con- mation of nerves (polyradiculopathy). Symptoms of encephalitis in- tact and via organ transplantation. Initial infection with CMV in adults clude dizziness, neurological dysfunction and seizures. Symptoms can be associated with mononucleosis-like symptoms (primarily fe- of polyradiculopathy include numbness and tingling (similar to that ver and body aches) or without symptoms at all. Incidence of infec- of peripheral neuropathy) and loss of muscle control. Again, some of tion rises with age, and by adulthood, nearly half the population in these symptoms look exactly like those of other opportunistic infec- developed countries is infected with this virus. CMV infection rates tions, so sometimes CMV infection may be overlooked.
are much higher among people in high-risk groups for HIV infec-tion: nearly 100% in gay men with about 25% – 40% actually devel- DiagnosisThe factors most associated with CMV disease are a CD4+ cell count of oping CMV disease. The risk of developing CMV disease increases as less than 50 and at least one other prior opportunistic infection. Recent CD4+ cell counts decline. It is believed that CMV disease is due to the studies have shown that anyone with detectable CMV levels using PCR reactivation of dormant CMV in immune compromised people. Up (polymerase chain reaction test, the same technique used to detect HIV to 90% of people with HIV have evidence of CMV infection at autopsy, levels) or are either antigen or culture positive for CMV are at higher while about 10% is CMV considered to be the primary cause of death.
risk for developing CMV disease, though a measurable CMV PCR level, However, CMV infections do not typically cause serious or life-threaten- by itself, does not always correlate with active infection and symptom- ing disease unless a person has a severely weakened immune system.
CMV can infect almost every part of the body. But in people with HIV, it seems to preferentially infect the eye in the form of CMV retinitis.
CMV Retinitis. The most common CMV-related condition in people with HIV is retinitis (inflammation of retina), characterized by a loss of visual acuity (sharpness) or blind spot in the eye. Left untreated, CMV retinitis will lead to blindness.
CMV Colitis. Colitis, or inflammation of the colon, is another CMV- related condition. People with this condition experience diarrhea, weight loss, loss of appetite and fever—symptoms which are so com- mon in people with advanced HIV infection as to make it difficult to distinguish from other diseases of the intestinal tract. Diagnosis of CMV in the colon is difficult, and it requires at least 4–6 weeks to demonstrate that CMV is the cause of colitis and not other possible infections such as bacteria, fungi, parasites or other viruses. Because many of symptoms of CMV colitis are similar to symptoms of other opportunistic infections, it may be difficult to diagnose CMV colitis in its early stages. If you suspect that you have symptoms as outlined above, talk to your healthcare provider.
Add’l Information - 8/98; 12/98; SF Area and International 415-558-9051 - Fax 415-558-0684 Administrative Offices 415-558-8669 - Web Site www.projectinform.org 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 ________________________________________________________________________________________________ In one study, an oral formulation of ganciclovir (1000mg three times results are preliminary, there is already good indication that these daily) was able to reduce the incidence of new CMV disease by 50% new oral anti-CMV drugs may soon eliminate the need for routine compared to placebo, while in another study, there was no clear differ- intravenous therapy. They also appear to offer much greater promise ence between the two groups. In present form, oral ganciclovir is poorly retained by the body, probably accounting for its weak activity. How- Treatment of CMV retinitis usually involves two stages—induction therapy ever, it is obvious to almost all physicians that since the advent of and maintenance therapy. Induction therapy is used to control the active HAART, the incidence of new CMV infection has dropped dramatically, spread of CMV and usually requires higher and/or more frequent dosing on its own and without the use of CMV preventive therapies. The effec- than what is required after the disease is initially brought under con- tiveness of HAART in preventing new CMV disease is probably linked to trol. Once the spread of CMV is controlled, then a lower and/or less its ability to raise and maintain CD4+ counts well above the level at frequent dose is used to prevent CMV from reactivating. Previously, induction therapy was started for two weeks before going on mainte- One of the fears around CMV preventative therapy is that if some- nance therapy however, most CMV specialists now feel that it is essen- one does develop CMV during therapy, then their treatment options tial to control the CMV before starting maintenance therapy. This are severely limited as a result of resistance and cross-resistance might mean staying on induction therapy for more than two weeks.
(resistance to one drug results in resistance to other drugs) to other Intravenous Ganciclovir (Cytovene)
CMV therapies. However, this does not appear to be the case basedon results from a CMV prevention study that showed that people and Foscarnet (Foscavir)
Ganciclovir and foscarnet are administered through an intrave-
who received oral ganciclovir but developed CMV disease respondedwell to CMV treatment.
nous (directly into the vein) central line (catheter), which has to besurgically implanted. Both drugs are systemic (throughout the body) and thus can prevent CMV from spreading throughout the body. At Several therapies are approved for CMV disease treatment, including: present intravenous ganciclovir is preferred over foscarnet as first-line therapy for CMV as it generally has fewer side effects and is • daily intravenous (directly in the vein) infusions of ganciclovir better tolerated. One study actually demonstrated that foscarnet showed a significant survival benefit over ganciclovir (12.6 months compared to 8.5 months) in people with CMV retinitis, although • ganciclovir implant (Vitrasert, a device containing ganciclovir this may be due to foscarnet’s own possible anti-HIV activity. How- that is surgically implanted inside the eye and lasts for about 6-12 ever, neither visual function nor CMV progression time differed between the two groups, and foscarnet was associated with more • intravenous cidofovir (Vistide).
toxic side effects. Subsequent studies have shown no difference in • fomivirsen (Vitravene), an antisense product designed to be in- survival time between people receiving foscarnet or ganciclovir.
Induction therapy differs slightly between the two drugs. Ganciclovir Of these options, the ganciclovir implants (Vitrasert) generally pro- is given intravenously (5mg/kg) twice daily for at least two weeks.
vides the longest lasting protection from new or spreading CMV Foscarnet is administered intravenously (usually 90mg/kg) twice infection. Because it is implanted directly in the eye, however, it has daily for at least twoweeks. Foscarnet administration must be moni- no effect on the incidence of CMV elsewhere in the body.
tored because of its high toxicity and accompanied by infusion ofsaline hydration to decrease the drug’s side effects on the kidneys.
The oral form of ganciclovir is sometimes used for maintenance Administration of foscarnet sometimes requires hospitalization for a therapy (after a course of intravenous therapy controls the spread of few days so that a person can be carefully monitored for side effects.
CMV) and for prevention of CMV disease. A number of other therapies One possible advantage of foscarnet is that it appears to have some degree of direct action against HIV as well as CMV, and as such, it may • intravitreal cidofovir (a version of cidofovir injected directly into add to the overall anti-HIV effects of therapy. This could be particu- larly advantageous for people who are having difficulty keeping their • valganciclovir, which is a new version of oral ganciclovir that is viral load under control with standard HIV antivirals. However, some far better absorbed into the bloodstream; researchers feel this advantage is counteracted by the complexity of • Glaxo Wellcome 1263, an oral drug (taken by mouth, as a pill, using the drug as well as its side effects.
rather than as an injection or infusion).
Following successful induction, maintenance therapy continues with Of these, the two new oral drugs (valganciclovir and GW 1263) seem the administration of the drug indefinitely at a lower dosage.
to offer the greatest promise of advances against the disease. Though Ganciclovir is usually given intravenously at a dose of 5–10mg/kg 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 _________________________________________________________________________________________________ Page 3 of 9 once a day while foscarnet is given intravenously at a dose of 90– ligram per deciliter), creatinine clearance of 55mL/min or less, or a 120mg/kg per day during the maintenance phase.
urine protein level of 100mg/dL or more, all of which indicate kid-ney toxicity levels. People with decreased kidney function should use Recent research concluded that a combination of ganciclovir and a reduced dose of cidofovir (3mg/kg).
foscarnet significantly delayed progression of CMV retinitis com-pared to use of either alone. However, volunteers had a significantly more side effects and poorer quality of life due to the longer infusion Oral ganciclovir is approved for maintenance treatment of CMV retini- times of the two drugs, and no survival benefit was associated with tis. Although only 6% of the drug is maintained in the bloodstream the combination therapy. It is likely that such combination intrave- when taken orally, there is less risk of developing catheter-related sep- nous therapy will remain appropriate only in those instances when sis since the oral drug requires no central catheter. The oral drug is slightly less effective than the intravenous drug in preventing relapseof CMV disease and causes no additional side-effects. Because the oral Both ganciclovir and foscarnet have activity against other herpes drug is not well absorbed, large amounts are required and blood levels viruses, with foscarnet being commonly used to treat acyclovir-resis- of ganciclovir are much lower when the drug is taken orally compared to blood levels achieved when the intravenous form is used. As a result, People with catheters should carefully inspect the site of catheter oral ganciclovir is not recommended for induction treatment of CMV insertion each day, and report any evidence of irritation or infection, retinitis. There is some concern that using the oral drug, with its low tenderness or fluid discharge immediately to the physician. Men who availability in the body, may lead to more rapid development of are on foscarnet should carefully dry the penis after urination to ganciclovir resistance and possible cross-resistance with other anti- reduce the chance of ulceration associated with foscarnet usage. People CMV drugs (making those drugs ineffective in treating CMV).
receiving foscarnet should closely monitor for electrolyte and min- A new version of oral ganciclovir, which is commonly referred to as val- eral imbalances. Additionally, people on foscarnet should monitor ganciclovir, is currently in studies. Valganciclovir is better absorbed serum creatinine levels for signs of kidney toxicities and people with into the bloodstream and the ganciclovir levels found in blood is kidney impairment may require a lower dose of foscarnet.
similar to that of the intravenous formulation. Valganciclovir is likely Cidofovir (Vistide)
to be used as both induction therapy (twice daily dosing) as well as Cidofovir is also approved for the treatment of CMV retinitis. Cidofovir maintenance therapy (once daily dosing) thereby eliminating the use has the advantage over other intravenous drugs in that it is adminis- of intravenous drugs (and catheters) when treating CMV disease.
tered only once (5mg/kg) a week for induction therapy and once Ocular Ganciclovir Implants (Vitrasert)
(5mg/kg) every two weeks for maintenance therapy and therefore The ganciclovir implant, which is also approved for the treatment of does not require a surgically implanted catheter, avoiding possible CMV retinitis, involves inserting a pellet containing ganciclovir di- bacterial infections. Cidofovir has shown activity in laboratory stud- rectly in the eye. This therapy has three advantages to intravenous ies against CMV and other herpes viruses, including zoster, Epstein- CMV therapy: it provides highly localized therapy for CMV retinitis; Barr virus and human papilloma virus. It is also active against CMV eliminates the need for daily intravenous infusions and the perma- that is resistant to either ganciclovir or foscarnet, but is unlikely to be nent insertion of a catheter (with associated risk of bacterial infec- active against CMV that is resistant to both of these drugs.
tions); and reduces systemic (through out the body) toxicity. How- While no studies have compared cidofovir to other CMV therapies, ever, the implants will not provide protection against CMV spreading such as ganciclovir or foscarnet, results from the studies that have to the other eye or to other parts of the body. Additionally, in some been conducted are encouraging. Approval of cidofovir was based on studies, there have been a higher rate of retinal detachments among two studies showing that immediate cidofovir therapy can delay CMV people receiving the implants compared to those receiving systemic therapy, such as intravenous ganciclovir or foscarnet.
Cidofovir has a narrow dose range in which it is effective but does not A study conducted at the National Eye Institute (NEI) found that the cause significant side effects. In some studies side effects included ganciclovir implants significantly delay progression of retinitis (by proteinuria (high protein in the urine), neutropenia (abnormally low 226 days) in people with previously untreated CMV retinitis. This neutrophil cell counts) and peripheral neuropathy (pain or tingling demonstrated an advantage over deferred treatment as well as over in the hands, feet and/or legs). The major side effect of cidofovir, if intravenous administered drugs (47 and 53 days for intravenous used improperly, is serious kidney toxicity. To reduce this risk, people ganciclovir and foscarnet). In the NEI study, there was a high inci- are given intravenous saline solution and a drug called probenecid dence of people who developed CMV in the other eye (50% at six before cidofovir infusions. Additionally, cidofovir should not be used months) or outside the eye (31%). However, another study compar- in people with serum creatinine levels of more than 1.5mg/dL (mil- ing intravenous ganciclovir and implants showed no significant dif- 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 ________________________________________________________________________________________________ ference in either the development of extraocular (outside the eye) and drug interactions. Systemic ganciclovir suppresses the bone mar- CMV disease or development of CMV retinitis in the other eye. There row, while foscarnet and cidofovir can be very hard on the kidneys. Large was no significant survival advantage with implant use, but there is amounts of drug are required to make sure the drug crosses the blood/ little reason to expect that treating CMV retinitis should provide a eye barrier to have an effect against CMV retinitis. Typically, excessive survival benefit since the infection threatens sight, but not life.
amounts of drug must be used systemically to reach adequate levelsinside the eye. Both foscarnet and IV ganciclovir require infusions These studies suggest that the use of the ocular implants greatly ex- daily and the insertion of a permanent catheter into a major artery.
tends the durability of treatment, resisting further retinitis in the in- Such catheters bring with them a high risk of bacterial infections, such fected eye two to three times longer than currently available therapies.
as sepsis, which can be difficult to treat in immunosuppressed people.
A recent study found the combination of ganciclovir implant and oral Foscarnet also requires long, slow infusion times. Intravenous cidofovir ganciclovir was able to significantly delay the progression of CMV retini- has some advantages in that it requires infusion only once every other tis as well as protect against CMV from spreading to other body parts.
week, thereby eliminating the need for a surgically implanted catheter.
The unquestioned advantage of the implants is the improvement in The advantages of local therapy include a much improved quality of quality of life for the person diagnosed with CMV retinitis. Prior to life and greatly reduced risk of side effects. Ocular (eye) implants of the implants, such a diagnosis was grim, requiring the insertion of an ganciclovir are inserted once every six to eight months. Intravitreal infection-prone catheter, followed by daily intravenous infusions for injections occur more frequently but are still less burdensome than life. The implant is a relatively simple, outpatient procedure that daily infusions and the constant risks associated with catheters and protects the infected person for up to twelve months without any systemic treatment. Both approaches also seem to suppress disease other form of therapy. Simply eliminating the catheter and the risk of in the eye much longer than the standard intravenous ganciclovir or associated bacterial infections reduces the apparent gravity of a CMV foscarnet treatments. The only real question about their use is the diagnosis. However, some caution that implants can cause transient risk of CMV outbreaks elsewhere in the body. Studies have so far decreases in vision and increased risk of retinal detachment.
failed to clearly quantify this risk.
Fomivirsen (Vitravene, ISIS 2922)
As more therapies become available for the treatment of CMV retini- ISIS Pharmaceuticals is developing an antisense drug that works by tis, it becomes more essential to weigh the risks and benefits of all the binding a portion of CMV RNA and preventing viral replication.
different options. Old, new and soon-to-be-approved treatment op- Twenty-two people (28 eyes) with CMV retinitis who had failed all tions differ in their usefulness for different CMV-related conditions.
other anti-CMV therapies were given different doses of fomivirsen by In addition, their impact on quality of life and in drug-related side direct injection into the eye once weekly for three weeks, followed effects differs greatly. It is possible that some approaches may pro- thereafter by a maintenance dose every other week. The drug may long survival more so than others, but due to the difficulty of con- cause eye inflammation, which can be treated by topical steroids, ducting the large trials needed in people with advanced disease—the and increased risk of retinal detachment. Some people maintained only place where CMV is a major problem—this effect may never be retinal stability without disease progression for over 50 weeks. How- clearly understood. Thus, each individual must face the prospect of ever, the results are not directly comparable to larger studies of other choosing a therapy based on factors such as quality of life, risk of side treatments, and it is too early to know how fomivirsen will fit into the effects, risk of wider spread of the infection and more or less frequent need for additional therapy. Though not clearly documented, it is possible that new, more powerful treatments for HIV disease may One of the most pressing questions for the treatment of CMV retinitis is themselves improve the effect of treatment for CMV infections.
whether localized therapy (treating a specific site, like the eye) is suffi- cient or superior to systemic (whole body) therapy. All intravenous and Induction therapy with intravenous ganciclovir for enteritis or coli- oral drugs are considered systemic whereas the ganciclovir implant, tis usually lasts a week longer than for CMV retinitis, but the doses are intravitreal cidofovir and Fomivirsen are “local” therapies, only treat- the same. Induction treatment may be extended until the infection ing CMV in the eye. Since CMV disease can effect the entire body, many clears. Foscarnet will be chosen if platelet counts fall below 20,000/ physicians believe that some form of systemic therapy is required.
ul, or if ganciclovir therapy doesn’t work.
Others believe that only CMV retinitis warrants constant treatment andthat outbreaks of CMV elsewhere in the body can be handled if and Because CMV-related colitis is difficult to diagnose, most CMV drug when they occur. The potential benefit of systemic therapy is that they studies have focused on retinitis. Some small studies have included will provide protection against CMV disease spreading into the other volunteers with colitis and encephalitis (inflammation of brain tis- eye or into other parts of the body. However, this comes at a high cost, as sue). One small study showed survival benefit with a ganciclovir and all the intravenous drugs currently available can cause severe side effects foscarnet combination therapy. A 1988 trial also established the value 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 _________________________________________________________________________________________________ Page 5 of 9 of high dose foscarnet (200mg/kg once daily for three weeks) in treating CMV colitis. It also remains to be seen if oral ganciclovir will A growing number of researchers and physicians believe the most be more effective at combating CMV colitis than intravenous drugs.
effective and least invasive way to treat CMV retinitis may be to use a localized therapy for the retinitis in combination with an oral therapy Drug interactions need to be considered when formulating a treat- for protection throughout the rest of the body. Intravenous cidofovir ment strategy against CMV. Ganciclovir and AZT can cause neutrope- may also play an important role in this regard due to its infrequent nia, although it is reversible with small doses of G-CSF or GM-CSF.
dosing). This approach combines the high effectiveness and good Absolute neutrophil counts (ANC) should be closely monitored when quality of life associated with local therapy along with reasonable ganciclovir is used in combination with other bone marrow suppres- protection against CMV outbreaks elsewhere in the body. Some stud- sive therapies. Ganciclovir and ddI and/or d4T may increase the risk ies are already underway to determine if this is the overall best way of treating CMV retinitis. Even this strategy, however, may be changed ifthe initial promise of new oral drugs like valganciclovir is sustained.
Foscarnet is highly toxic to the kidneys, and people on foscarnet should This could shift the burden of therapy almost entirely to oral medica- not take other drugs that affect the kidneys, such as amphotericin B, tions. However, FDA approval of all new drugs for CMV is hampered the aminoglycosides (like amikacin), intravenous pentamidine and by the low level of incidence of CMV infection in the era of HAART.
certain anti-inflammatories. People should also be aware of the in- The success of HAART in preventing CMV infections has made it creased risk of peripheral neuropathy (pain or tingling in the feet, extremely difficult to recruit enough people with new CMV to com- hands and/or legs) from the combination of foscarnet and ddI.
Cidofovir is administered with probenecid which prevents kidney tox- There is a growing number of preliminary reports of people who have icity. The combination of ganciclovir and probenecid slows down the stopped CMV maintenance therapy because of sustained CD4+ cell elimination of ganciclovir and sometimes results in generalized sei- count increases realized as a result of triple-drug combination of anti- zures. Foscarnet elimination is also affected by probencid, so combina- HIV therapy including a potent protease inhibitor, without immedi- tions of cidofovir with other currently approved intravenous therapies ately relapse of CMV disease. However, it is still not known how long are potentially dangerous. Also, probenecid may interact with other this will last, how soon after initiation of HAART it can be done, or commonly used HIV medications. Drugs causing kidney toxicity (see whether everybody who have CD4+ cell count increases can stop their foscarnet drug interactions) should not be used with cidofovir. People CMV maintenance therapy. Most researchers agree that there is likely planning to use cidofovir should allow at least seven days to “wash out” to be much individual variation in these regards, probably based on such other agents before beginning cidofovir therapy. Particularly, pre- the degree of immune function which was lost prior to initiating the vious use of foscarnet may increase the likelihood of kidney toxicity.
triple-drug anti-HIV regimen. Many researchers believe that the spe- Drugs that are injected directly into the eye are unlikely to interact cific types of CD4+ cells, which provide protection against opportu- with other drugs that are administered intravenously or orally, but nistic infections, may be lost due to immune deterioration and these such potential interactions should not be immediately dismissed.
cells do not necessarily return, at least in the short-term, when CD4+ For more on potential drug interactions, call the Project Inform cell counts increase as a result of triple-drug therapy. The longer term National HIV/AIDS Treatment Hotline at 800-822-7422.
picture, however is less clear, with some researchers reporting success-ful return of many cells types previously thought to be lost.
Where to Get ItGanciclovir, foscarnet, cidofovir, and the ganciclovir implants are New information on resistance to CMV therapies indicate that people available by prescription. Most states also cover these drugs through resistant to ganciclovir are more at risk of developing resistance to their AIDS Drug Assistance Program (ADAP). For information on foscarnet. If people are resistant to both ganciclovir and foscarnet, your state ADAP eligibility and to find out if these therapies are cov- then they are at greater risk of developing resistance to cidofovir.
ered through your state’s ADAP formulary, contact your state depart- People with sight-threatening CMV retinitis should consider aggres- ment of public health. Information is also available through the AIDS sive therapy such as a ganciclovir implant in addition to systemic Treatment Data Network at 1-800-734-7104. People who lack insur- intravenous therapy. People without sight-threatening CMV retinitis ance, Medicaid, ADAP coverage or personal financial ability to pur- may be able to use therapies that allow for a better quality of life such chase the drug can sometimes gain access to therapies through the as initial therapy with intravenous drugs and subsequent maintenance manufacturers Patient Assistance Program. For infor on patient As- with oral or local therapy. While issues of resistance make the decision sistance Programs for: ganciclovir (oral/IV) call 1-800-285-4484, making process more complex, people should discuss these issues ganciclovir implants call 1-800-843-1137, foscarnet call 1-800-488- with their physicians to determine the most suitable course of therapy.
3247 and cidofovir call 1-800-445-3235.
2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 ________________________________________________________________________________________________ THERAPY
ADVANTAGES
DISADVANTAGES
Immunosuppressive and can cause many possible drug Physicians have the most experience with this interactions; poor quality of life; surgically implanted drug; should prevent CMV from spreading elsewhere catheter for daily infusions; risk of bacterial infections Requires careful monitoring due to side effects; poor Physicians have experience using this drug; should quality of life; requires surgically implanted catheter prevent CMV from spreading elsewhere with risk of bacterial infection; may have overlappingtoxicity with cidofovir Should prevent CMV from spreading elsewhere; Requires large amount of drug; may be less effective; may contribute to more rapid development of resistance Must be taken with probenecid to minimize side effects; Should prevent CMV from spreading elsewhere; possibility of drug interactions between probenecid and commonly used HIV medications; may have overlappingtoxicity with foscarnet Significantly increases time before relapse; improved Will not prevent CMV from spreading elsewhere; fewer quality of life; no risk of systemic side effects; no physicians have experience with this device; may cause need for catheters and risk of bacterial infections an increased risk of retinal detachment In laboratory tests it is active against ganciclovir Requires frequent direct injection into the eye; may cause an increased risk of retinal detachments Will not prevent CMV from spreading elsewhere; Infrequent direct injection into the eye; somewhat Intravitreal cidofovir (localized) optimal frequency and dose of injections not yet known; high doses may lead to irreversible toxicity;may cause an increased risk of retinal detachment Simple to use, possibly equal or better in effectiveness than IV GCV; systemic coverage; effects compared to systemic therapy, thus greatly enhancingquality of life issues. Disadvantages of local therapy are that they • People with a sustained CD4+ cell count of less than 50, who have do not prevent the spread of CMV disease into other parts of the had a prior opportunistic infection, are most at risk for develop- body, and particularly do not prevent the spread of CMV into the • People with detectable CMV levels or are either antigen or culture positive for CMV are also at higher risk for developing CMV disease.
• There is no standard of care for the maintenance therapy of • There remains controversy over whether people should start CMV disease. Generally, maintenance therapy is only started preventative therapy against CMV with the current version of after the active CMV disease is controlled.
• Maintenance therapy should be continued indefinitely to pre- vent the infection from returning. In most cases, the infection • There is no standard of care for the treatment of CMV disease.
will likely return if maintenance therapy is discontinued.
Several drugs are approved for the treatment of CMV (see table • It is currently not known if CMV maintenance therapy can be below for advantages and disadvantages for each therapy).
stopped if an individual on an aggressive triple-drug anti-HIV • Advantages of systemic (e.g. intravenous) anti-CMV therapies are regimen, including a potent protease inhibitor, realizes sub- that they may prevent CMV disease throughout the body. Disad- stantial CD4+ cell count increases. This issue is currently un- vantages of these therapies is that they have more side effects der study. However, it is probably safe to assume that it would be than local (treating only the site of disease, like the eye) and impact very unwise to stop CMV maintenance therapy unless CD4+ cell quality of life (some require a surgically implanted catheter).
increases as a response to aggressive anti-HIV therapy weresustained for a substantial period of time (6 months to 1 year) • Advantages of local (i.e. treating only the problem site , like the and HIV RNA levels remained very low, below the limit of detec- eye in the case of CMV-retinitis) are that they have far fewer side For permission to reprint this, or other Project Inform materials, contact 415-558-8669 or [email protected] 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 In a study designed to examine cytomegalovirus (CMV)-specific immune re-sponses in people stopping CMV retinitis maintenance therapy, it was found that 9/13 people developed vitritis (an inflammation in the eye) in the same eye PI Perspective #25, September 1998 as that of the retinitis. The vitritis was associated with decreased vision and ledto blindness in some people. In general, people developed vitritis about three months after stopping CMV maintenance therapy and there was no evidence of re-emergence of the retinitis. Interestingly,people who had higher CD4+ cell count increases and stronger immune responses specific to cytomegalovirus were morelikely to develop vitritis. The researchers believe that ironically people with stronger immune systems are still responding toresidual cytomegalovirus in the eye and thus are experiencing this inflammatory response. If the inflammation is because ofresidual CMV, it may be possible to minimize the risk of vitritis by continuing on CMV maintenance therapy for a longerperiod of time. For those people who do decide to stop CMV maintenance therapy, it is advisable to be routinely monitoredby an eye specialist (ophthalmologist). One caveat to these results is that the study was conducted at the University ofCalifornia, San Diego where they routinely use intraocular injections (injection directly into the eye) of cidofovir (Vistide) totreat people with CMV retinitis. This is not the approved route of administration for this drug. Additionally, there have beenanecdotal reports of vitritis in people treated with intravenous (injections into the veins) cidofovir while on HAART.
The Food and Drug Administration recently approved a new treatment for cytomegalovirus (CMV) retinitis, an opportunis- tic infection affecting people with advanced HIV disease. Left untreated, CMV can lead to blindness. Fomivirsen (Vitravene,formerly ISIS 2922) is given by injection directly into the eyeby an ophthalmologist (eye specialist) every two or four weeks.
The recommended dose is 330µg on days 1 and 15 during the initial phase of treatment (when CMV is still spreading). Itis then given once monthly during the maintenance phase (when CMV is not actively spreading but requires therapy toprevent it from reactivating). Studies show fomivirsen works equally well in people with newly diagnosed CMV retinitis asin those receiving other CMV therapies.
Since fomivirsen blocks CMV from replicating through a different foscarnet (Foscavir) and cidofovir (Vistide) in suppressing and pre- mechanism than that of other approved CMV retinitis therapies, people venting the recurrence of active CMV retinitis. However, the ganciclovir who have developed resistance to other therapies may still benefit implant (Vitrasert), which is surgically implanted into the eye and from this drug. Because fomivirsen is administered directly into the slowly releases ganciclovir, has demonstrated much longer lasting eye, it does not cause any systemic (throughout the body) side effects.
anti-CMV retinitis effects. Nonetheless, fomivirsen is a welcome addi- However, in some studies, some people had retinal detachments. In tion to the arsenal of anti-CMV therapies, especially because of its one study that employed a higher dose in people with newly diagnosed ability to work after resistance develops to other CMV therapies.
CMV retinitis, some developed retinal stippling (spots in the retina) which resulted in some loss of peripheral vision. The fact that it works A new 500mg capsule of ganciclovir (Cytovene) is now available for only locally in the eye also prevents the drug from suppressing CMV use in the prevention and maintenance treatment of CMV disease. Pre- infections elsewhere in the body, a limitation not shared by most other viously, oral ganciclovir was only available in 250mg capsules, and when used for prevention or maintenance of CMV disease, required Though there have been no results directly comparing fomivirsen with twelve capsules a day (1,000mg three times a day). This new 500mg other approved therapies, the results from studies so far suggest it is capsule will reduce by half the number of pills needed daily.
comparable in effectiveness to intravenous ganciclovir (Cytovene), National Hotline 800-822-7422SF Area and International 415-558-9051 - Fax 415-558-0684 This Addenda Sheet represents information that is new and has Administrative Offices 415-558-8669 - Web Site www.projectinform.org not yet been incorporated into a Fact Sheet or Discussion Paper. 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 ________________________________________________________________________________________________ Oral ganciclovir is poorly absorbed into the body and therefore is the drug remains controversial because of conflicting study results.
considered second-line therapy for the maintenance of CMV disease.
More importantly, the success of HAART today in partially restoring However, because all other systemic therapies for CMV are adminis- immune function has diminished the need for preventive use.
tered intravenously (directly into the vein), many people opt for oral A new formulation of oral ganciclovir, sometimes known as ganciclovir because it does not require a surgically implanted cath- proganciclovir or valganciclovir, is currently in studies. This new for- eter, which is accompanied by a risk of serious bacterial infections.
mulation is so much better absorbed by the body that the sponsor Oral ganciclovir is also sometimes used for prevention of CMV disease hopes it may eventually eliminate the need for intravenous therapy in people with severely compromised immune systems, but this use of Cytomegalovirus (CMV) is a potentially life-threatening virus and is the lead-ing cause of blindness in people with HIV disease. Recent evidence suggests that the incidence of CMV is down. A number of studies are looking at the feasibility of stopping therapy aimed at preventing recurrence of CMV disease (or maintenance therapy). Results so far suggest the need for caution whenone thinks about stopping maintenance therapy. They underline the continued importance of CD4+ cell counts as the primary measure for determining one’s immediate risk of developing CMV.
One study reported on 17 people who stopped their CMV mainte- the ability to combat CMV (called CMV-specific lymphoproliferative nance therapy after getting an increase in CD4+ cell counts from responses). No participant who maintained CD4+ cell counts above HAART. All of the participants had CD4+ cell counts over 70 and had 100 had CMV reactivation. This study suggests it may be wise to wait healed CMV retinitis, an inflammation of the eye that can cause blind- until CD4+ cell counts go above 100 for several months before dis- ness if left untreated. Despite continuing their HAART regimen, five continuing CMV maintenance therapy. Also, people who have a sub- of the seventeen participants had their CMV retinitis reactivated after sequent decline in CD4+ cell counts to below 75 may want to recon- being off maintenance therapy for 6-28 months. All volunteers who sider starting CMV main-tenance therapy before CMV reactivation had CMV reactivation had seen their CD4+ cell counts return to be- recurs. In many ways, these findings reflect the general guidelines low 50 and typically had higher HIV levels compared to people who employed for CMV before the use of highly potent antiviral regi- did not have reactivation. Also, five of the six people with CMV reac- mens. Earlier guidelines typically suggested taking CMV prevent tivation had very low levels of the immune system marker that has medications when the CD4+ count fell below 75.
Eye doctors (ophthalmologists) have recently observed the appearance of eye inflammation in people who have experienced remission of cytomega- lovirus (CMV) retinitis in response to highly active antiretroviral therapy (HAART). This eye inflammation is currently called Immune Recovery Uvei- PI Perspective #28, September 1999 tis (IRU). Uveitis is an inflammation inside the eye which can result in sig-nificant vision loss. IRU has only been observed in people who started HAART and had a significant increase in CD4+ cell counts and who have stopped their anti-CMV therapies. Additionally, IRU onlyoccurs in eyes that were previously diagnosed with CMV retinitis.
One hypothesis for IRU is that there may still be low level CMV replica- (around the eye) injections of prednisone and methylprednisolone tion in the eye. The newly invigorated immune response may be at- (Depo-Medrol). In most instances, when these medications were tacking the CMV and causing inflammation. There are several un- knowns at this point. It is not known if people who have the ganciclovir A large observational study has started at the Studies of Ocular Com- implants (Vitrasert) to treat CMV are as likely to develop IRU because plications from AIDS (SOCA) sites and it is hoped that this study will the implants are better able to control CMV replication. It is also not be able to assess the incidence and prevalence of IRU, the cause of IRU known if IRU will improve if someone resumes CMV therapies.
and strategies to treat it. In the meantime, people who previously had Ophthalmologists have tried a few different therapies to treat IRU CMV retinitis should consider the risk of IRU when thinking about with limited success, including systemic prednisone, periocular 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461 Long-awaited results from a study of treating CMV (cytomegalovirus) retini- tis show that a new formulation of oral (by mouth) ganciclovir, known as valganciclovir, is as effective as the intravenous (IV, injection into the vein) version of the drug. This is the first time that an oral drug for treating CMV has been shown to be as effective as the IV version.
The use of valganciclovir results in similar drug levels in blood asthose produced by the IV form. This is a major improvement over the The major points from Treating CMV
currently approved oral form of ganciclovir (Cytovene), which is • A new oral drug, valganciclovir shows effectiveness in treating CMV.
hampered by poor absorption into the bloodstream and consequently • This is the first oral drug shown to be as effective as standard IV weak control of CMV. The standard version of oral ganciclovir is only therapy for treating this condition.
approved for maintenance therapy (to prevent CMV from recurring • Future studies will examine how useful this drug is in preventing in people who have already been treated for the disease) and for preventing initial CMV disease (though the data for prevention useare weak and conflicting). It is not approved for treating the activedisease.
Study ResultsThe study included 160 people with active CMV disease and CD4+ Other PI Publications
cell counts averaging around 25. About 25% of the volunteers werenot on highly active anti-HIV therapy when they started. Participants Project Inform (PI) has developed more than a hundred publica-tions including Fact Sheets, Discussion Papers, Charts and the PI received either 900mg of valganciclovir twice a day for three weeks Perspective (the journal of Project Inform) designed to make infor- followed by one week of 900mg daily or 5mg/kg of IV ganciclovir mation about medical therapies, research advances and living with twice a day for three weeks followed by one week of 5mg/kg daily.
HIV disease approachable. All of these publications are availablethrough the Project Inform’s National HIV/AIDS Treatment Hotline. There was no difference in rates of CMV disease progression betweenthe two groups at the end of four weeks. About 10% in each group continued to have progressive CMV disease, and about 65% in each group responded well in controlling the virus. There are no data yet to show whether valganciclovir is equivalent to the IV formulation in Building a Doctor Patient Relationship the time to relapse (when CMV recurs).
A large study is planned to look at the effectiveness of preventive CMV treatment with valganciclovir. It will study the drug’s use in people without CMV disease who have measurable CMV levels in their blood (called CMV PCR positive). Several studies have shown that CMV PCRpositive people are more likely to develop CMV disease than CMV This list is updated as new information develops, but it does not include all the materials available. Please call the ProjectInform Hotline, or check out the website below for even more If this strategy works, it will mean that only people at risk for devel- oping CMV disease would need to use preventive therapy. This isunlike the current standard in which people consider CMV preven- tion therapy based solely on their CD4+ cell counts. This will reduce the cost of HIV care as well as spare people from risking the sideeffects of potentially unnecessary therapy.
National Hotline 800-822-7422SF Area and International 415-558-9051 - Fax 415-558-0684 This Addenda Sheet represents information that is new and hasnot yet been incorporated into a Fact Sheet or Discussion Paper. Administrative Offices 415-558-8669 - Web Site www.projectinform.org 2001 Project Inform, Inc., 205 13th Street #2001, San Francisco, CA 94103-2461

Source: http://www.verbinnen.net/PDF/cmv.pdf