Try, Try Again
First protease inhibitor, saquinavir, returns in stronger formulation
When the first protease inhibitor, Hoffmann-La Roche's saquinavir (Invirase®), won F.D.A. approval in late 1995, it was widely hailed as a major advance in the treatment of HIV infection. But healthcare professionals soon discovered that the drug's effectiveness was hampered by its low bioavailability: saquinavir had few side effects, even at high doses, but it was hard to get enough of the drug into the bloodstream to suppress viral replication to undetectable levels. As newer, better-absorbed protease inhibitors were approved -- indinavir (Crixivan®) and ritonavir (Norvir®) in 1996, nelfinavir (Viracept®) in 1997 -- they supplanted saquinavir as first-line therapy.
Although saquinavir proved to be the least potent protease inhibitor when used alone or in combination with nucleoside analogs, it works well in combination with ritonavir. In patients who cannot tolerate the side effects of other, more powerful protease inhibitors -- and in those who have failed initial combination therapy with one of those protease inhibitors -- the combination of saquinavir and ritonavir is often an option. In this unique pairing ritonavir functions not only as an antiretroviral agent but as a kind of booster rocket, one that increases the bioavailability of saquinavir by a factor of 40!
The F.D.A. has now approved a new formulation of saquinavir -- a soft-gelatin capsule that is much more easily digested than the old hard-gelatin version. The new formulation, named Fortovase®, delivers eight to nine times as much saquinavir to the bloodstream as Invirase® did, making this protease inhibitor a more appealing option for patients who are not doing well on their current therapy.
What this means for you:
The soft-gel formulation of Roche Laboratories' protease inhibitor has been shown to reduce viral load to undetectable levels in 81% of patients over 16 weeks of therapy when used in combination with AZT and 3TC. During this same period the study subjects' CD4 counts increased by 170.
These results were obtained in an open-label trial of 41 treatment-naïve patients with viral loads greater than 10,000 (mean: 63,408) and CD4 counts greater than 100 (mean: 412). Fortovase® was given at a dose of 400 mg. three times a day, and the AZT and 3TC were given at the currently recommended doses. The soft-gel capsule formulation of saquinavir was generally well tolerated, with only two patients withdrawing from the study due to adverse effects. The most common complaints were nausea, diarrhea, vomiting, and headache.
Ongoing clinical trials are testing this new formulation of saquinavir in combination with nucleoside analogs, NNRTIs, and other protease inhibitors. A number of studies have already established that the addition of ritonavir to a saquinavir-containing regimen increases blood levels of the latter drug -- a synergistic effect that translates into increased efficacy. It is reasonable to assume that regimens that combine ritonavir and the soft-gel capsule formulation of saquinavir will provide even higher serum concentrations of active drug, leading to even greater antiretroviral activity.
Rubbing Out Herpes
Cidofovir gel heals herpes lesions that do not respond to Zovirax®
For people with herpes outbreaks that are unresponsive to oral acyclovir (Zovirax®), the standard treatment for this common viral infection, a new topical gel may offer relief. In a clinical trial of 30 people who had at least one herpes lesion that failed to improve after 10 days of treatment with oral acyclovir, 30% of the study participants who applied cidofovir gel to their lesions once daily showed complete healing of the lesions, and another 20% had their lesions reduced to less than half the original size. By contrast, study participants who used a placebo gel showed no clinical response at all. These results suggest that cidofovir gel may offer a treatment option for patients whose herpes outbreaks cannot be controlled with acyclovir. The topical gel is certainly an advance in terms of convenience, given that the current back-up treatment for unresponsive herpes outbreaks, foscarnet, must be administered intravenously.
Monthly gammaglobulin infusions prevent infections in people with CD4 counts less than 100
A team of researchers from New York's Cabrini Medical Center has conducted a small study which strongly suggests that prophylactic treatment with intravenous gammaglobulin can significantly reduce the number of infections experienced by people with CD4 cell counts under 100. The 18 people involved in this study received infusions of gammaglobulin (40 milligrams per kilogram of body weight) once a month for 18 months. Over the course of the study, 43 infections developed in the group receiving the gammaglobulin. During this same period 178 infections were noted in a control group of patients with similar clinical profiles who did not receive gammaglobulin.
These results led the researchers to conclude that prophylactic treatment with intravenous gammaglobulin may reduce mortality and improve quality of life for people with advanced HIV disease. Due to the relative inexpensiveness of gammaglobulin treatment, this form of prophylaxis is also likely to reduce healthcare costs.
Resistance Is Futile
First test for HIV resistance to nucleoside analogs is now available
With so many therapeutic options now available to physicians and patients alike, the all-important question is: Which combination of antiretroviral drugs will work best for you? People who are just beginning antiretroviral therapy can be expected to respond well to any of a number of multidrug regimens. People who have tried many drug combinations over the years have fewer options -- because they have, almost certainly, developed resistance to one or more of the drugs they were assigned.
The longer you have been on therapy -- and the more drugs you have tried and abandoned -- the more important it is you know your "resistance profile." Because no one drug has proven effective at suppressing HIV for long, it is crucial to employ a combination of drugs that will reduce viral activity to minimal -- preferably undetectable -- levels. The ideal drug combination is the one that suppresses viral replication as completely as possible for as long as possible with as few side effects as possible.
What is needed is, in essence, a full-court press: each of the chosen drugs must be effective against whatever strains of virus are present in your body. If the team of drugs you and your care-provider have fielded against HIV has even one weak player, the virus will take full advantage of that lone weakness to beat the whole therapeutic team.
A test is now available that can help determine how resistant a viral isolate is to any of the nucleoside analogs. Developed by Murex Technologies, the so-called LiPA HIV-1 RT genotypic resistance assay identifies nucleoside analog-induced mutations in HIV DNA. These mutations indicate whether a patient's viral isolate has developed resistance to AZT, ddI, ddC, or 3TC. Genotypic resistance to d4T is not readily identified.
What this means for you:
Some researchers have cautioned clinicians against attaching too much significance to the information gained from genotypic testing, because these assays read only a small portion of the DNA of HIV. Phenotypic assays, which are still being developed, provide information regarding future treatment options for the viral isolate that is assayed -- but these highly sophisticated tests are difficult to perform, expensive, and labor-intensive. Until a less costly and more widely available phenotypic assay is developed, healthcare providers are limited to the information that genotypic testing provides. This information may only be as good as an accurate history of a patient's prior antiretroviral therapy.
The genotypic assay's main utility is in identifying drugs that will not be effective against the viral strains in a particular person. Often, this information can also be obtained from a thorough history of prior anti-HIV medication combined with knowledge, derived from viral-load monitoring and on-going clinical care, about a patient's response to that treatment. A three-fold increase in viral load is generally accepted as an indicator that antiretroviral therapy is failing.
Genotypic testing does have significant limitations. The treatment information suggested by the genetic mutations that the assay reveals is not conclusive, and the LiPA HIV-1 RT test only identifies possible HIV resistance to nucleoside analogs, not possible future treatment options. Until phenotypic testing can be made faster and easier, and until tests are developed to identify mutations that indicate resistance to the various protease inhibitors and NNRTIs, the information provided by first-generation genotypic assays will be of limited value to healthcare professionals and their patients when they are making decisions about changes in antiretroviral therapy.
Another Use for the Common Condom
Condoms can reduce the transmission of CMV in people with HIV
Cytomegalovirus (CMV) is one of the most dreaded AIDS-related opportunistic infections. It can take hold at many sites in the body, but it most commonly occurs in the gastrointestinal system, where it can cause severe digestive problems, and in the eyes, where it can cause blindness. Until recently, the spread of CMV to and from women with HIV had been more thoroughly studied than transmission involving men with HIV.
Now a study of 723 HIV-positive men at L'Hôpitale du Kremlin-Bicetre in France has correlated CMV status to the participants' sexual behaviors before being diagnosed with HIV. Routine condom use during the six months preceding diagnosis was associated with a 60% reduction in risk of being positive for CMV. Indeed, even occasional condom use during the six months prior to diagnosis reduced the risk of being CMV-positive by 50%. The researchers conclude that regular use of condoms can prevent CMV infection in HIV-positive men.
What this means for you:
CMV is a nearly-ubiquitous organism, commonly found in people with or without HIV, but like many AIDS-related opportunistic infections it produces serious illness only in people with seriously weakened immune systems. Because CMV is so widespread, most people with HIV already have it when they are diagnosed. For them, avoiding active infection is primarily a matter of maintaining their immune systems above a certain level: CMV rarely strikes someone with a CD4 cell count over 100, and it is relatively rare in individuals with CD4 counts over 50. Prophylaxis can sometimes prevent illness in CMV-infected individuals with very low CD4 counts.
For the small percentage of people with HIV who are not already infected with CMV, prevention is crucial. If a person with HIV is fortunate enough to be uninfected with CMV, he or she can take precautions to avoid contagion. As noted above, the consistent use of condoms is an important way to avoid CMV infection.
Warts and All
HPV infections, often linked with cancer, proceed faster in people with HIV
There is now strong evidence to show that human papillomaviruses (HPVs), the sexually-transmitted viruses that cause genital and anal warts, also cause cervical cancer -- and HPVs may be a major factor in anal cancers as well. Studies also show that HPV infection proceeds much more rapidly in people with HIV. Therefore, people with HIV -- especially those who have, or who have had, genital or anal warts -- are encouraged to be particularly vigilant for early signs of abnormalities that may foreshadow cancer. In addition to regular gynecological examinations, HIV-positive women should have yearly pap smears, which will identify abnormal cell growth at an early stage. For the same reasons both women and men with HIV should have anal swabs taken and analyzed.
Valley of the Dolls
After rash of HIV prescription errors, pharmacy group urges caution
A non-profit watchdog group, U.S. Pharmacopeia, notes that its Medication Errors Reporting Program has logged a significant increase in prescription errors over the last few months. What is causing the rash of errors? The chief cause of confusion, according to U.S.P., is that so many HIV drugs have similar-sounding generic names, and even more of these drugs have brand names that sound alike.
Common mistakes include mixing up Norvir® and Retrovir® or confusing the antiretroviral lamivudine with lamotrigine, an anticonvulsant. In order to minimize confusion, the U.S.P. is recommending that pharmacists and their staffs avoid the use of abbreviations, use both generic and brand names when ordering drugs, and keep similarly-named drugs in separate areas.
What this means for you:
Care-providers can do their part to reduce the chances that drugs will be dispensed in error by avoiding abbreviations -- and by using both the generic and brand names for drugs -- when writing prescriptions. Patients should be aware that dispensing errors do occur, and they should know what drugs they have been prescribed. Make certain that what you receive from your pharmacist is what the doctor ordered. Question any change in the appearance of the medications you are taking.
To help my patients keep their medications straight, I urge them to make a daily dosing chart for themselves. A shirt cardboard or a sheet of stiff paper serves well for this purpose. I tell my patients to paste sample pills directly onto this chart, and to change the chart whenever their regimen changes. This simple device helps prevent confusion about which pills the patient is taking, how many he or she is taking, and when they are to be taken.
Susan Shea, R.N., F.N.P.
UCSF School of Nursing
San Francisco, CA
Last February we alerted readers to the dangers of taking a protease inhibitor in combination with rifampin (Rifadin®) or rifabutin (Mycobutin®). Because all of these drugs are metabolized at the same location in the liver, both rifampin and rifabutin increase the speed at which protease inhibitors are processed by the liver -- causing the amount of protease inhibitor in the bloodstream to drop below effective levels, thereby promoting the development of drug-resistant viral strains (see "Drug-Interaction Warnings," Vol. 1, No. 1, page 6).
More recently, warnings have been issued about possible interactions between the protease inhibitors and the three most popular anticonvulsant drugs: carbamazepine, phenobarbital, and phenytoin. In theory, anyway, using any of these anticonvulsants with a protease inhibitor may reduce the amount of the protease inhibitor circulating in the body, and this may allow suppressed HIV to rebound. Conversely, the use of protease inhibitors -- particularly ritonavir (Norvir®) and nelfinavir (Viracept®) -- may cause blood levels of the anticonvulsants, particularly carbamazepine, to escalate to toxic levels.
Concerns about potential drug-drug interactions have made some care-providers wary about prescribing delavirdine (Rescriptor®), one of the two F.D.A.-approved non-nucleoside reverse- transcriptase inhibitors, in combination with fluconazole (Diflucan®), an antifungal agent used to combat many common opportunistic infections, including thrush. However, a recently published study has shown that the two drugs can be taken together, and that no adjustment is necessary to the dosage of either drug.