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Decmber 1997

  1. A new treatment for refractory herpes
  2. More on how HIV enters cells
  3. New formulation of saquinavir
  4. First test for HIV resistance to nucleoside analogs is available
  5. HIV found in lymph tissue of patients with "undetectable" viral levels
  6. Gammaglobulin prevents infections in patients with low CD4 counts
  7. The immune system vs. HIV
  8. Drug-Drug Interactions: An Update

A new treatment for refractory herpes

Cidofovir gel heals herpes lesions that do not respond to acyclovir

For patients 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.

Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Carey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. Journal of Infectious Diseases 1997; 176: 892-898.

More on how HIV enters cells

New discoveries may guide future research

In 1984, several scientists at the National Cancer Institute embarked on a project that many of their colleagues considered a waste of time and resources. Their plan was to examine the DNA of individuals exposed to HIV, to determine if there were genetic differences between individuals whose disease progressed slowly and those known as rapid progressors. It took more than a decade for this "needle-in-a-haystack" research to bear fruit: reports concerning cell-surface molecules that assist HIV in gaining entry into cells began to appear in the literature in the mid-1990s (see "Genetic mutation appears to confer immunity to HIV," Vol. 2, No. 5, and "How HIV penetrates CD4 cells," Vol. 2, No. 6).

It was well known that HIV used the CD4 receptor as a point of entry into cells, but other cites remained unidentified until Dr. Stephen J. O'Brien and his colleagues at the Laboratory of Genomic Diversity at the National Cancer Institute identified a protein receptor now called CKR5 or CCR5, found on T-lymphocytes, as a target of HIV.

Investigators determined that mutant versions of the CCR5 protein existed, and they found that individuals whose DNA codes for the mutant version of CCR5 make a protein that is "truncated," i.e. shorter than the normal protein. This abbreviated version of CCR5 occurs in some, but by no means all, individuals who have been exposed to HIV but have not been infected. The mutant version of the protein receptor is never found in people who have been infected, however.

Some of the same researchers have amplified these original findings, and they will soon publish a paper describing their results. This group analyzed a cohort of 3,003 patients with AIDS -- and this time they focused their attention on another cell-surface protein, CCR2. Like CCR5, CCR2 ordinarily functions as a receptor for chemokines, which are chemical signals that cells use to communicate. Unlike CCR5, CCR2 is not found with increased frequency in individuals exposed to, but not infected by, HIV. However, people with the CCR2 mutation were found to have a slower course of disease progression.

In general, the presence of the altered CCR2 protein translated into a two-to-three-year postponement of the median time to a diagnosis of AIDS. This finding was consistent among participants in several large studies, including the Multicenter AIDS Cohort Study, the San Francisco City Cohort Study, and the Multicenter Hemophilia Cohort Study. In all analyses, the mutant version of CCR2 was more prevalent in individuals whose disease progressed slowly than it was in rapid progressors. The investigators estimate that 29% of long-term survivors (those who do not progress to a diagnosis of AIDS for a decade or more after they are first infected) owe their indolent disease course to the presence of these mutant surface proteins. These findings, according to the authors, can be put to use in designing novel treatments to prevent cellular infection by HIV.

Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. In press.

New formulation of saquinavir, Fortovase®, has eight to nine times the bioavailability of Invirase®

Soft-gel capsules overcome principal therapeutic limitation of oldest protease inhibitor

When the first protease inhibitor, Hoffmann-La Roche's saquinavir, won F.D.A. approval in late 1995, it was widely hailed as a major advance in the treatment of HIV infection. But clinicians 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 and better-absorbed protease inhibitors were approved -- indinavir and ritonavir in 1996, nelfinavir 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 (see "Enhancing saquinavir levels with ritonavir," Vol. 3, No. 3). In patients who cannot tolerate the side effects of other, more powerful protease inhibitors -- and in those who have failed their initial multidrug antiretroviral regimen -- the combination of saquinavir and ritonavir offers an important therapeutic option. In this unique pairing ritonavir functions not only as an antiretroviral agent but as a pharmacokinetic agent, 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 has enhanced phermacokinetic properties. The new formulation delivers 300% more saquinavir to metabolic sites than the old formulation did, making this protease inhibitor a more appealing option for patients who are not doing well on their current therapy.

Dr. Harold A. Kessler, author of "The Next Generation of Antiretroviral Agents -- An Update," in this issue, and a member of the editorial advisory board of HIV Newsline, comments:

In a study presented at this year's ICAAC meeting, the soft-gel formulation of Roche Laboratories' protease inhibitor was shown to reduce viral load to undetectable levels (400 copies/mL in this study) in 81% of patients over 16 weeks of therapy when used in combination with ZDV and 3TC. During this same period the study subjects' CD4 counts increased by 170 cells/mm3.

These results were obtained in an open-label trial of 41 treatment-naïve patients with viral loads greater than 10,000 copies/mL (mean: 63,408) and CD4 counts greater than 100 cells/mm3 (mean: 412). Fortovase® was given at a dose of 1200 mg t.i.d. and the ZDV 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 serum 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. Patients now taking ritonavir and Invirase® can be safely switched to ritonavir and Fortovase® at the same dose, 400 mg b.i.d.

First test for HIV resistance to nucleoside analogs is available

Genotypic assay can help clinicians determine treatment-induced resistance to nucleoside analogs

With so many therapeutic options now available to physicians and patients alike, the all-important question is: Which particular combination of antiretroviral drugs will work best for a particular patient? Individuals 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 a patient has been on therapy -- and the more drugs that individual has tried and abandoned -- the more important it is to know the patient's "resistance profile." Because no one drug has proven effective at suppressing HIV for long, it is crucial to employ a combination of drugs that suppresses viral replication as completely as possible for as long as possible with as few side effects as possible.

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.

Dr. James O. Kahn, co-author of "The Problem of Protease Resistance," Vol. 3, No. 3, and a member of the editorial advisory board of AIDS Care, comments:

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, practitioners 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 resistance to nucleoside analogs, but 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 clinicians and patients making decisions about changes in antiretroviral therapy.

HIV found in lymph tissue of patients with "undetectable" viral levels

A blow to hopes that HIV can be eradicated in some patients

Data presented at last October's ICAAC meeting in Toronto seem to seriously challenge hopes that HIV can be eradicated through very early, very aggressive multidrug therapy. Dr. Robert Siliciano and his colleagues at John Hopkins University examined the prevalence of, and decay dynamics in, resting CD4 cells that harbor HIV DNA. Early estimates of the length of time needed to achieve eradication with a highly suppressive antiretroviral regimen ranged from two to three years (see "Highlights of the 4th Conference on Retroviruses," Vol. 3, No. 1, pages 19-20). More recently this estimate has been increased to between 6 and 10 years, with some investigators flatly declaring that eradication would never be possible.

What Siliciano found is that a tiny pool of latently infected lymphocytes -- less than 0.01% of resting CD4 cells with a "memory" phenotype -- persist after as much as 30 months of HAART. While the majority of resting CD4 cells contain integrated HIV DNA that is defective and therefore harmless, a small but significant percentage of these cells can be stimulated to produce infectious virus under certain laboratory conditions.

The Johns Hopkins team examined 22 patients who had been treated with protease inhibitor-containing HAART regimens for 30 months or longer and who had maintained plasma HIV RNA levels below 200 copies/mL, the lower limit of detection of most commercially available assays. The resting lymphocytes in these patients were isolated and purified. Specimens from four patients proved inadequate for viral isolation, but the remaining 18 produced infectious virus when stimulated with radiation and phytohemaglutanin. "It is clear that replication of competent virus can persist in these cells," Siliciano concludes, "and while we do not know the precise decay characteristics of these cells, we do know that their half-life exceeds nine months."

Siliciano R. Latent reservoir of HIV. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract S-36.

Dr. David Hardy, a member of the editorial advisory board of HIV Newsline, comments:

These findings serve as a sobering reminder of the highly invasive and insidious nature of HIV infection, and they may cast cold water on the theory, advanced by Dr. David Ho and others, that it might be possible to eliminate HIV entirely in at least some infected individuals, if their infection could be caught early enough and treated aggressively enough. What makes Dr. Siliciano's data particularly dismaying is that he found no correlation between the length of time his subjects were on HAART therapy and the number of infectious cells they harbored -- suggesting that viral clearance and eventual eradication may not be functions of the length of time a patient is on therapy.

Gammaglobulin prevents infections in patients with low CD4 counts

Monthly infusions reduce morbidity in advanced HIV disease

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 counts below 100 cells/mm3. The 18 people involved in this study received infusions of gammaglobulin (40 mg/kg 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.

Fontana L, Castro C, Mullen M. Intravenous gammaglobulin in the prevention of infections in severely immunocompromised AIDS patients. 1997 International Scientific Assembly of the American College of Chest Physicians, New Orleans, 1997. Abstract 14S.

The immune system vs. HIV

Tipping the balance in favor of viral control

A group of researchers affiliated with Harvard Medical School has demonstrated that the immune system is capable of mounting a vigorous and effective attack against HIV under certain circumstances -- and individuals who manifest this response appear to be capable of keeping HIV at bay for long periods of time. So-called long-term non-progressors, some of whom have virtually intact immune systems more than a decade after they were infected with HIV, may benefit from the development of a type of T cell called a "cytotoxic T lymphocyte," or CTL, that specifically attacks HIV. CTLs mount this attack by punching holes in the protective membranes of HIV-infected cells, killing the cells and the virus within them.

According to Rosenberg and his colleagues, these HIV-specific CTLs persist in the body even after highly-active antiretroviral therapy has reduced serum HIV RNA concentrations below the level of detection of the commercially available assays. The persistence of surveillance CTLs is what is referred to as a "memory" response.

The most important target of the CTLs, the Harvard researchers note, is p24 antigen, a protein in the core of HIV. Indeed, there is an inverse correlation between viral load and the strength of the CTL response against p24. On the other hand, the investigators found only a weak association between the strength of the CTL response and the level of CD4 cells -- a finding that may help to explain why CD4 cells are not an especially good surrogate marker for viral load.

This important piece of research has any number of tantalizing clinical implications. The investigators studied three individuals who were identified and treated during the acute phase of HIV infection, a time when viral proliferation is occurring at extraordinarily high levels. All three received HAART before they had developed antibodies to the virus -- and because viral replication was largely suppressed during this period, all three developed strong anti-HIV CTL responses.

The authors contrast these findings with data from patients who began HAART well after the period of acute infection and who failed to develop anti-HIV CTL. The implication is that post-exposure HAART therapy, even if it fails to eradicate the virus completely, may result in a more indolent form of HIV infection. In short, HAART may tip the balance a bit more in favor of the immune system.

Although preliminary, these intriguing findings do strongly support the "hit early, hit hard" philosophy of antiretroviral therapy. It may well be impossible to eradicate HIV in infected individuals (see the preceding item in this Newsline section, "HIV found in lymph tissue of patients with 'undetectable' viral levels"). But that does not mean that early, aggressive antiretroviral therapy cannot alter the course of HIV disease in some patients. Larger clinical studies are clearly warranted, to investigate whether the immune response to HIV can be significantly enhanced by HAART during the brief window of opportunity that follows acute exposure to the virus.

Rosenberg SR, Billingsley JS, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1 specific CD4+ cell responses associated with control of viremia. Science 1997; 218: 1447-50.

Drug-Drug Interactions: An Update

Use caution when mixing protease inhibitors and anticonvulsants

The addition of protease inhibitors to combination therapy has revolutionized the fight against HIV. It has also complicated the care of people with HIV. The increased use of combination antiretroviral therapy has led, predictably enough, to an increase in the number of adverse drug-drug interactions seen in people taking these multidrug regimens. Sometimes these adverse interactions occur when antiretrovirals are taken in combination. (We know, for example, that the NNRTI nevirapine reduces serum concentrations of some protease inhibitors.) More often these adverse interactions occur when antiretrovirals are taken in combination with agents used to combat AIDS-related opportunistic infections -- such as the drugs used to fight tuberculosis (see "Guidelines for the Administration of Protease Inhibitors and Rifampin in HIV-Positive Patients with Tuberculosis," Vol. 3, No. 5).

Last February we alerted readers to the dangers of taking a protease inhibitor in combination with rifampin or rifabutin (see "Drug-interaction warnings," in AIDS Care, Vol. 1, No. 1, page 6). Because all of these drugs are metabolized at the same location in the liver, both rifampin of 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.

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 and nelfinavir -- may cause serum levels of the anticonvulsants, particularly carbamazepine, to rise to toxic levels.

Practitioners who treat people with HIV should therefore confer with a neurologist before prescribing an anticonvulsant to one of their patients. It may be preferable to use either of two other anticonvulsants, gabapentin and lamotrigine, since they are not metabolized at the same place in the liver -- but neither is approved by the F.D.A. for single-agent use as an anticonvulsant. Of the protease inhibitors, indinavir is predicted to have the most minimal interaction with any of the anticonvulsants.

Brooks J, Daily J, Schwamm L. Protease inhibitors and anticonvulsants. AIDS Clinical Care 1997; 9: 87.

Delavirdine and fluconazole can be taken together without adjusting doses

Concerns about potential drug-drug interactions have made some practitioners wary about prescribing delavirdine, one of the two F.D.A.-approved non-nucleoside reverse-transcriptase inhibitors, in combination with fluconazole, an antifungal agent used to combat many common opportunistic infections, chiefly oral candidiasis. However, a study recently published in Antimicrobial Agents and Chemotherapy has shown that the two drugs can be taken together, and that no adjustment is necessary to the dosage of either drug.

Borin MT, Cox SR, Herman BD, Carel BJ, Anderson RD, Freimuth WW. Pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. Antimicrob Agents and Chemother 1997; 41: 1892-7.

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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.