Makers of two protease inhibitors okay twice-daily dosing
Data presented at the 5th Conference on Retroviruses and Opportunistic Infections indicate that it may be possible to take indinavir (Crixivan®) or nelfinavir (Viracept®), protease inhibitors that are commonly taken in combination with reverse-transcriptase inhibitors, twice a day -- instead of three times daily, which is how they are currently taken. (For an overview of the conference, as seen through the eyes of an advocate for people with HIV who is herself living with AIDS, see Dawn Averitt's editorial, "Highlights of the 5th Conference on Retroviruses," in this issue.)
At the conference Merck & Co., makers of indinavir, and Agouron Pharmaceuticals, makers of the most recently approved protease inhibitor, nelfinavir, announced the results of preliminary studies demonstrating that these drugs reduce viral load when taken twice daily as long as these agents are used in combination with RT inhibitors. The concern was that dosing these drugs at wider intervals would create a "peak and trough" effect -- meaning that the amount of drug circulating in the body could drop to subtherapeutic levels toward the end of each 12-hour dosing cycle, a situation that encourages the development of drug-resistant viral strains. This does not appear to be the case. When the current daily dose of each drug is split into two doses taken every 12 hours instead of three doses taken every eight hours, the anti-HIV effects of the drug are maintained.
What this means for you:
If adopted, these simplified dosing schedules for indinavir and nelfinavir will make life easier for people who take either of these drugs as part of a combination therapy regimen. We know that viral replication is successfully suppressed when the combinations of antiretroviral drugs an individual is taking are present at therapeutically effective levels in the body. When the medications are not present at effective levels, viral replication rises -- and so does the risk that drug-resistant forms of HIV will begin to develop.
We also know that careful compliance with one's assigned antiretroviral regimen is essential, if viral suppression is to be successfully sustained. It follows that any simplification of the daily dosing demands of combination therapy will enhance compliance. This is especially true of the protease inhibitors. Of the three classes of antiretroviral agents, the protease inhibitors require the most careful and timely dosing. They also impose the greatest dietary restrictions: nelfinavir, for example, must be taken with food, while indinavir must be taken on an empty stomach with plenty of fluids (or with one of the low-fat, low-calorie snacks listed in "Foods You Can Eat When You Take Crixivan," the Pull Out and Save feature in the October 1997 issue of AIDS Care).
Cutting the dosing of both of these protease inhibitors from three times a day to twice a day should make it easier for people with HIV to stick to their assigned dosing schedules -- and this, in turn, should promote maximal suppression of viral replication. This preliminary information is exciting, and it should generate optimism among people with HIV and those who provide their continuing care. However, it may be premature to adopt this simplified regimen until we have more information on how the participants in these trials fare on twice-a-day dosing. (Those data will be presented in early July, at the 12th World AIDS Conference in Geneva, and we will report them in the August issue of AIDS Care.)
In the interim, individuals who are now on a combination antiretroviral regimen that includes one of these protease inhibitors should not switch from thrice-daily to twice-daily dosing without consulting with their primary care providers.
As importantly, anyone who opts for the convenience of a twice-a-day regimen for indinavir or nelfinavir should be aware that strict adherence to this simplified dosing schedule is imperative. The convenience of a twice-daily regimen is greater -- but so is the risk that viral replication will occur if a dose is missed, because the intervals between doses are longer and the troughs at the end of each dosing cycle are deeper.
New two-month TB prophylaxis regimen is as effective as yearlong therapy
Because people with weakened immune systems are particularly susceptible to tuberculosis, the AIDS pandemic has fueled a worldwide resurgence of TB infections (see "Aggressive treatment programs defuse a global TB crisis" in the April 1997 issue of AIDS Care). Fighting TB in people with HIV is difficult for exactly the same reasons that combatting HIV infection is difficult: treating TB in individuals with active infection, and preventing infection in those with latent disease, involves taking a multidrug regimen on a set schedule for an extended period of time -- and failure to adhere carefully to one's assigned regimen can lead to the development of resistance to the very drugs that are commonly used to treat the disease.
We now know that people with HIV who were born in Mexico, Vietnam, China, Haiti, India, South Korea, and the Philippines are at high risk of developing TB, because the disease is endemic in those countries -- and exposure is all but universal. Residents of New York City, New York State, and the District of Columbia are also at increased risk of infection for the same reason. In addition, the homeless and incarcerated, and all those who abuse alcohol and drugs, are at heightened risk (see "TB or Nor TB" in the October 1997 issue of AIDS Care). To make matters worse, these HIV-positive individuals are likely to develop a strain of tuberculosis that is resistant to most of the drugs now used to treat active TB infection.
Current guidelines call for prophylactic administration of isoniazid, every day for a full year, to prevent active infection from developing in HIV-positive individuals who have been exposed to TB and have latent disease. Preventive therapy is not necessary for those who have not been exposed to tuberculosis, irrespective of CD4 count (see "Should You Be on Preventive Therapy Against TB?" in the October 1997 issue of AIDS Care). Fortunately for all people with HIV who require TB prophylaxis, prevention has just been made considerably simpler; at the 5th Conference on Retroviruses, an international team of physicians reported that a much shorter course of prophylaxis seems to be just as effective in forestalling outbreaks of TB in people with HIV.
In a six-year study that involved almost 1,600 people with HIV in the U.S., Mexico, Haiti, and Brazil -- all of whom tested positive for TB exposure -- researchers compared the standard prevention regimen (isoniazid daily for one year) with a two-month regimen of daily rifampin and pyrazin-amide. During post-treatment follow-up that averaged three years, the two-drug, two-month regimen was found just as effective as the year-long, single-drug regimen in preventing active TB infections. Of the 791 participants given the two-month rifampin/pyrazinamide treatment, 18 developed confirmed cases of TB and another nine had probable cases that could not be confirmed. Of the 792 participants who took isoniazid for a year, 24 developed confirmed cases of TB and three had probable cases.
As might be expected, more patients were able to complete the shorter regimen -- 80%, as opposed to the 68% who finished the yearlong treatment. Not only will this new regimen make it easier to prevent active tuberculosis in people with HIV, it should make it possible to carry out TB-prevention programs in parts of the world where completing a yearlong program is not feasible.
A six-drug regimen proves to be surprisingly effective in heavily pretreated patients
Many people with HIV have now been on antiretroviral therapy for five to seven years, and some for even longer. They began with AZT monotherapy, moved on to combinations of nucleoside analogs, then added newer drugs as those became available. Some of these extensively treated individuals have, by now, been on so many different combinations that they have developed resistance to many or all of the currently approved drugs. Their best hope of achieving maximal suppression of viral replication lies with investigational drugs now in development (see "The Next Generation of Antiretroviral Agents" in the February 1998 issue of AIDS Care). However, a new study indicates that a combination of six agents, all now on pharmacy shelves, can largely suppress the replication of HIV, even in patients who have developed resistance to several of these drugs.
At the 5th Conference on Retroviruses a group of Australian doctors presented the results of a study they had conducted using a combination of d4T (Zerit®), ddI (Videx®), 3TC (Epivir®), nevirapine (Viramune®), nelfinavir (Viracept®), and the soft-gel capsule formulation of saquinavir (Fortovase®). Twelve patients were enrolled in this small pilot study. All had been heavily pretreated, all had broken through on their first protease-inhibitor-containing regimen, and all were failing their current combination-therapy regimen. Of the six drugs used in the trial, only nevirapine and nelfinavir were new to the participants.
Three people in the study had to drop out when they proved to be intolerant to one or more of the drugs used in this salvage regimen. (All three adverse reactions were to drugs for which these patients had documented intolerance.) The nine patients who remained in the study achieved undetectable viral loads (which in this study meant less than 400 HIV RNA particles/mL), and their viral loads remained undetectable through the twelfth week of the study. All nine showed increases in CD4 cell counts, but those increases varied widely: from 30 cells all the way up to 370 cells.
What this means for you:
This six-drug regimen is undeniably complex and demanding, but it does seem to offer hope to people with HIV who have developed broad resistance to most of the available antiretroviral agents and who have, as a result, exhausted many of their pharmaceutical options. This pilot study reported results for only 12 weeks and enrolled only 12 patients, so we must be cautious about interpreting the data it has yielded, but the good results achieved by the nine patients who were able to tolerate this salvage regimen suggest that this multidrug combination -- and others like it -- may reduce viral burden and boost CD4 counts in extensively treated individuals, including those who may have developed high-level resistance to several of the components of such combination therapies.
An important characteristic of this regimen was the fact that it contained two drugs to which the study participants had never been exposed, nevirapine and nelfinavir. As we now recognize, the addition of several previously untried drugs is crucial to the success of a new antiretroviral regimen. In fact, adding two untried drugs may be a minimum requirement if a new regimen is to succeed.
It is important to bear in mind, in this regard, that while people with HIV may have only one really good shot at achieving potent and durable suppression of viral replication, this does not mean that they have only one shot. In the editorial in this issue of AIDS Care Dawn Averitt says that her theory of HIV therapy is that "each of us is dealt one wild card, which we can use at any time. That wild card is initial therapy, and we can play it early in the game or hold it back until the stakes are higher." As Dawn also observes, "We may get dealt only one wild card, but that does not mean that there are no more good cards to play once we've used our best one -- and we need to know what those winning combinations are." This six-drug regimen may be just such a combination.
Addition of leukemia drug to anti-HIV therapy shows promise
Can a relatively inexpensive and widely available cancer drug play a role in combating HIV? In preliminary trial results reported at the 5th Conference on Retroviruses, a team of American and Italian doctors suggested that the leukemia drug hydroxyurea -- in combination with ddI (Videx®) and d4T (Zerit®) -- may do just that.
In this trial, 42 people with HIV -- some of whom had previously been treated with nucleoside analogs and some of whom had not -- were given either hydroxyurea alone, hydroxyurea with ddI, or hydroxyurea, ddI, and d4T. After 28 weeks of treatment, all patients showed significant decreases in viral burden and increases in CD4 cells, but the best response -- in terms of clinical status, viral load, and CD4 count -- was seen in recipients of the three-drug combination.
When this team of researchers examined blood samples from the 42 participants, they found that treatment with hydroxyurea, ddI, and d4T had led to an increase in so-called naïve CD4 cells, which are essential to reconstitution of the immune system. The investigators speculate that adding hydroxyurea to a drug regimen may also retard the emergence of resistance to those drugs by further reducing viral load.
What this means for you:
The study is to continue for a full year, and the results cited here are very preliminary, but if the observed changes prove durable, hydroxyurea may present an interesting new treatment option. Unlike the two nucleoside analogs used in this trial, hydroxyurea has no direct anti-HIV activity. But when it is given in combination with ddI and d4T, it increases the intracellular concentrations of these agents and facilitates their activation inside infected cells, apparently slowing replication of the virus in the process.
Because it does not affect HIV directly, the virus should not develop resistance to hydroxyurea, thereby eliminating one of the thorniest problems of current antiretroviral therapy. By slowing replication of HIV, hydroxyurea may make it harder for the virus to develop resistance to ddI, d4T, and other agents. And last but not least, hydroxyurea would be a cheap addition to existing anti-HIV drug combinations, which commonly cost $1,200 to $2,000 a month: hydroxyurea costs only $30 for a 30-day supply.
Useful as hydroxyurea may prove to be, it is no miracle drug. In the largest study conducted to date -- a multicenter, placebo-controlled clinical trial that was described at the 5th Conference on Retroviruses -- the addition of hydroxyurea to a multidrug anti-HIV regimen did result in a decline in viral load, but it produced almost no increase in CD4 count. This poses a dilemma for those of us who treat people with HIV: we would like to see a better immunologic response to hydroxyurea before we begin recommending this agent to patients. Studies now underway should help clarify hydroxyurea's role in the treatment of HIV infection, and we should have a better idea of what we can expect from hydroxyurea-containing antiretroviral regimens after the 12th World AIDS Conference in Geneva this coming July. Until then, this drug should be reserved for patients who have broken through on HAART and who will now be treated with a ddI-containing regimen. It may also be used to treat primary infection.
Adding a protease inhibitor to your antiretroviral regimen may reverse dementia
The early evidence suggested that protease inhibitors were not very good at penetrating the central nervous system or the brain. This apparent shortcoming of these otherwise powerful anti-HIV agents was important because the CNS and the brain are reservoirs of HIV infection -- and antiretroviral drugs that do not reach these sites cannot kill all of the virus in the body. More recent evidence is leading us to revise this earlier assumption about protease inhibitors. In the newsline section of the last issue of AIDS Care we reported that the protease inhibitor indinavir (Crixivan®) does achieve measurable levels in the CNS (see "Protease inhibitor appears to cross blood-brain barrier" in the February 1998 issue). Now a study published in the Journal of the American Medical Association suggests that adding a protease inhibitor to an antiretroviral regimen that includes two nucleoside analogs (AZT, ddI, ddC, 3TC, or d4T) may arrest or reverse dementia in people with HIV.
Doctors at Yale University followed 16 people with HIV who were suffering from dementia while on antiretroviral regimens that included two nucleosides but no protease inhibitor. Magnetic resonance imaging of the brains of all 16 showed severe white-matter disease. Seven of the trial participants continued on their previous drug regimens, while nine added a protease inhibitor to theirs.
Monthly MRIs, taken over the next year, showed significant differences between the two groups of participants. Eight of the nine individuals who added a protease inhibitor to their anti-HIV therapy showed stabilization of their encephalopathy, with four showing almost total regression of the disease. One of the seven patients not taking a protease inhibitor showed no change in his condition over the course of the study, but the other six experienced both continued deterioration of the brain and increased neurocognitive difficulty. It is not known by what mechanism the addition of protease inhibitors to antiretroviral therapy was able to alleviate dementia, but the results of the small trial are nonetheless significant. Further study of this positive response to HAART is clearly warranted.
What this means for you:
Once HIV has entered the central nervous system and penetrated the brain, it can only be eradicated by drugs that cross what is known as the blood-brain barrier. Unfortunately, many drugs that are highly effective against HIV in the circulatory system have only limited efficacy in the CNS -- and given what we now know about the virus's ability to escape immune surveillance by insinuating itself into lymph and brain tissue, it seems clear that truly suppressive therapy must include an agent or agents that can penetrate these remote sites.
Many factors come into play when decisions are being made about initiating or changing antiretroviral therapy, among them the potency of the combination, its potential side effects, and how likely it will be to promote compliance on the one hand and resistance on the other. As a result, one aim of multidrug antiretroviral therapy is to combine drugs that are very good at killing HIV in the blood (protease inhibitors) with drugs that are very good at killing HIV in the CNS and other remote sites (AZT, abacavir, nevirapine). In this regard the mounting evidence that protease inhibitors may exert an antiretroviral effect across the blood-brain barrier is good news indeed.
In a more general sense, this report is significant because it bolsters our conviction that maximally suppressive antiretroviral therapy produces many benefits beyond reduction of viral load. As my colleague Dr. Judith A. Aberg reported in the Newsline section of the last issue of AIDS Care, HAART apparently contributed to the cure of long-standing MAC infections in four patients seen at San Francisco General Hospital (see "HAART Therapy Leads to Resolution of MAC Infection" in the February 1998 issue). As Dr. Aberg, a member of the editorial advisory board of AIDS Care, noted, these patients were able to discontinue their MAC therapy after a year of maximally suppressive antiretroviral therapy combined with standard treatment for M. avium infection -- and up to a year later these patients still have no clinical evidence of MAC.
Want to avoid oral thrush? Get yourself to a dentist!
A team of researchers from the University of Texas has shown that oral candidiasis, the common fungal infection better known as "thrush," is promoted by cavities in your teeth. Their results were published in the February issue of the Journal of the American Dental Association. The Texas team found that thrush was not only more common in people with HIV than in those without, it was also more prevalent in people with HIV who had cavities than in those who did not.
Cavities and other dental difficulties apparently act as reservoirs for Candida albicans, the fungus that causes thrush. The dentists therefore advise people with HIV to have frequent dental exams and be aggressive in treating any problems discovered. Even small cavities should be filled; teeth that are too decayed to be effectively treated should be pulled.
To avoid developing cavities in the first place, people with HIV, like everyone else, should brush their teeth and floss well after meals. People taking medications that cause dry mouth -- as some drugs used to treat HIV or opportunistic infections can do -- are warned to be especially vigilant, since dry mouth promotes tooth decay.
Back to the April 1998 AIDS Care contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication AIDS Care.