Dose Frequency Warning for Didanosine (Videx)
In October 1999 the US Food & Drug Administration (FDA) approved once daily dosing for Videx brand didanosine. The agency did so on the basis of a 24-week interim analysis of randomized trial BMS 148 comparing once-daily didanosine plus stavudine (Zerit) and nelfinavir (Viracept) to zidovudine, lamivudine (Epivir) and nelfinavir. That analysis showed no statistically significant difference between regimens in the percentage of patients with an unquantifiable viral load (less than 400 copies/mL). However, by week 48, the proportion of patients in the didanosine arm with viral loads below 400 copies/mL was 50% compared to 59% for those in the comparator arm. Also, 34% of patients in the didanosine arm had HIV RNA below 50 copies/mL compared to 47% in the comparator arm. This difference was statistically significant. The FDA has now recommended that Bristol-Myers Squibb, maker of didanosine, make the following change in the Videx package insert: "The preferred dosing frequency of Videx is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of Videx."
Updated Warning for Abacavir (Ziagen)
Recent reports indicate that severe or fatal hypersensitivity reactions can occur within hours after abacavir re-introduction in patients with no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy. Hypersensitivity reactions can include fever, rash, respiratory symptoms (cough, shortness of breath, sore throat), fatigue or malaise and gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain). Once abacavir is discontinued, hypersensitivity symptoms should resolve quickly. However, continuation or re-introduction of abacavir can lead to more severe symptoms within hours, and may include life-threatening hypotension and death. If abacavir has been discontinued for reasons other than symptoms of hypersensitivity, and if re-initiation of therapy is considered, the reason for discontinuation should be evaluated to ensure that the patient did not experience symptoms of a hypersensitivity reaction. If hypersensitivity is suspected, abacavir should not be re-introduced. If hypersensitivity symptoms are not identified, then re-introduction should be undertaken with caution. Patients should be aware that a hypersensitivity reaction can occur upon restarting abacavir. Therefore, this should be done only if medical care is readily available to the patient. Cases of abacavir hypersensitivity can be reported to the GlaxoWellcome Product Surveillance Department (888.825.5249) or to the FDA MedWatch program (800.FDA.1088).
Viral Reservoirs and Plasma Viremia, Another Type of "Disconnect"
For some time now, scientists have determined the existence of HIV reservoirs that highly active antiretroviral therapy (HAART) cannot eradicate. However, the pathogenic significance of these reservoirs is unclear. Previous work has shown that there is no correlation between the size of the reservoir and the kinetics of viral rebound during treatment interruption. In an article published in Nature Medicine (6:7, p. 757, 2000) scientists conclude that the viral reservoir does not account entirely for the early rebounding of plasma HIV during treatment interruption. In this study 9 patients, with viral levels of less than 500 copies/mL (by bDNA) for a mean of 21.8 months and less than 50 copies/mL on 2 consecutive viral load readings, had HAART interrupted. Using heteroduplex mobility and tracking assays, scientists concluded that 7 of these 9 patients had viral rebounds that differed genetically from the cell-associated virus found in their viral reservoir. The source of this rebounding virus could not be identified and the authors conclude "latent HIV in the resting CD4+ T cell compartment is a potentially important source of re-emerging virus, [but] is not the sole and often not the major source of viral rebound after discontinuation of therapy."
More on Viral Blips
An abstract presented at the XIII International AIDS Conference lends evidence that viral "blips" (transient and quantifiable increases in viral load) in HIV-infected patients may not predispose individuals to full-blown viral rebound. Research by Diane Havlir, MD, and colleagues (Abstract TuPeB3195) analyzed data from patients receiving zidovudine (Retrovir), lamivudine (Epivir), and indinavir (Crixivan) from the Merck 035 and ACTG 343 studies. The investigators defined a blip as a viral load greater than 50 copies/mL with a subsequent viral load less than 50 copies/mL in patients who had previously experienced an undetectable viral load after 24 weeks of anti-HIV therapy. Investigators defined rebound as 2 consecutive viral loads greater than 200 copies/mL. Blips were not associated with greater risk of viral rebound: 9 (9.3%) of 96 patients with blips experienced rebound compared with 20 (13.8%) of 145 patients without blips. Of additional note, only 8% of those with blips had virologic suppression below 2.5 copies/mL compared with 52% without blips (p=0.013).
HAART and Beyond
Scientists report in Nature Medicine (6:7, p. 762, 2000) the in vitro and in vivo effects of mycophenolic acid (MPA) on HIV replication. MPA inhibits inosine monophosphate dehydrogenase, an enzyme involved in the guanosine nucleotide synthesis pathway. Since abacavir is a guanosine inhibitor, MPA potentiates abacavir's action much in the same way hydroxyurea potentiates didanosine. In addition, scientists note that MPA selectively inhibits lymphocyte proliferation and thus, actually causes the death of activated CD4 T cells. Reducing the number of activated CD4 T cells also reduces the number of target cells available for HIV replication. In 3 of 6 patients taking HAART plus MPA, the frequency of peripheral blood T cells containing replication-competent virus was substantially reduced (1 log or more) as compared to controls taking HAART alone.
HIV Accelerates Immune System Aging
Researchers from the University of Calgary Health Sciences Centre in Alberta, Canada, have found that HIV infection is associated with shortening of telomeres (the ends of chromosomes) in peripheral blood mononuclear cells (PBMCs). They compared CD4 and CD8 T cells of 73 HIV-infected patients to those of 27 uninfected individuals. An inverse relationship was observed between telomere length and progression of immunosuppression. HIV infection was associated with a 5-fold or greater accelerated aging of PBMCs. For example, the telomere length of 37-year-old HIV-infected patients was similar to uninfected 75-year-old controls. Telomere shortening was also correlated with reduced PBMC proliferative ability. The research, published in AIDS (14:7, p. 771, 2000), indicates a possible mechanism behind the loss of T cells leading to AIDS symptoms.
Clinical Guidelines for Managing Dyslipidemia
Preliminary guidelines to help physicians manage blood lipid abnormalities ("dyslipidemia") in patients on antiretroviral therapy have been posted on the Web at aactg.s-3.com/pub/docs/lipid_guidelines.htm pending publication in the journal Clinical Infectious Diseases. These recommendations summarize the current understanding in this area and are based on existing guidelines for dyslipidemia.
Shorter Survival in HIV-Infected Women with Low Serum Albumin
A prospective cohort study has found that the baseline level of serum albumin is an independent predictor of mortality in HIV-infected women. Data were collected for 3 years from over 2000 HIV-infected women in the US enrolled in the Women's Interagency HIV Study. The report published in AIDS (14:7, p. 863, 2000) found that the 3-year mortality of women with serum albumin less than 35 g/L was 48%, while the 3-year mortality of women with serum albumin of 42 g/L or greater was 11%. Women in the lowest albumin level category had a 3.1 times greater risk of death than those in the highest albumin category. The reason for this is unknown. Serum albumin has a variety of functions in the body relating to the immune system and inflammation; it is also a measure of nutritional fat. The impact of HAART therapy on serum albumin levels was not evaluated since most of the study period of observation was prior to the widespread use of HAART. The researchers plan to review later data from this cohort to study the effects of HAART.
Gender and Viral Load
Researchers from the Johns Hopkins Medical Institutions assert that HIV-infected women might not be getting timely treatment because of therapy guidelines developed from research on men. At the XIII International AIDS Conference, Timothy Sterling, MD, and colleagues presented research indicating that women who start out with a lower viral load than men have the same risk of progressing to AIDS. Their study enrolled more than 3300 HIV-uninfected intravenous drug users, with 156 men and 46 women later seroconverting. The average viral load for the men was 50,766 copies/mL and the average viral load for women 15,103 copies/mL. Of the 29 men who developed AIDS, the average viral load was 77,822 copies/mL, while only 17,149 copies/mL for the women who developed AIDS. Since current guidelines suggest treating HIV-infected people only when their viral loads reach 20,000 copies/mL, Sterling postulates that women who are at risk of developing AIDS might not receive necessary treatment. This is an issue of considerable debate and more research is needed to reproduce these results and determine clinical significance. Abstract TuOrB402.
Guide to Clinical Care of HIV-Infected Women
A document entitled "Guide to the Clinical Care of Women With HIV: 2000 Preliminary Edition" has been posted on the Web (hab.hrsa.gov/womencare.htm). The Ryan White CARE Act program of the Health Resources and Services Administration has made this resource available to clinicians caring for women living with HIV/AIDS. This is a preliminary edition and comments, criticisms, corrections, suggested changes and other guidance are encouraged (contact information available on website).
The Centers for Disease Control and Prevention (CDC) recently issued a statement regarding a UNAIDS study of a product, COL-1492, which contains nonoxynol-9. The study, presented at the XIII International AIDS Conference (Abstract ThOrC660), investigated the use of COL-1492 as a possible microbicide or topical solution that could prevent the transmission of HIV and other sexually transmitted diseases. The researchers found that nonoxynol-9 did not prevent HIV infection and may actually have caused more transmission, as the women who used the nonoxynol-9 gel became infected with HIV at about a 50% higher rate than women who used a placebo. The CDC's statement on the study is available online, at cdc.gov/hiv, or by calling the National Prevention Information Network, at 800.458.5231.
Lopinavir (Kaletra) Update
Investigators at the XIII International AIDS Conference presented data on lopinavir, formerly known as ABT-378/r and now given the brand name Kaletra. In study M97-765, investigators treated 70 volunteers having a history of virologic failure to 1 protease inhibitor with lopinavir monotherapy for 2 weeks. They then added nevirapine (Viramune) and at least 1 nucleoside reverse transcriptase inhibitor (NRTI). At week 72, by an as-treated analysis, 88% of study participants achieved viral loads less than 400 copies/mL and 73% achieved levels less than 50 copies/mL. In another study, one of patients with a history of treatment with multiple protease inhibitors, 96% of the volunteers achieved viral loads less than 400 copies/mL at week 16 by on-treatment analysis. Of note, these volunteers were naïve to non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the contribution of efavirenz (Sustiva) to the virologic success of their treatment should not be underestimated. Still, an almost 100% rate of response is rare and encouraging in heavily pretreated individuals. If the response is sustained, a lopinavir containing combination holds great promise as third-line therapy. Lopinavir, coformulated with a small amount of ritonavir (Norvir), should come to market by late 2000 and is available now through expanded access. For more information on expanded access, call 888.711.7193. Side effects most commonly associated with lopinavir are diarrhea, elevated liver function tests and moderate increases in triglyceride and cholesterol levels. Abstract TuPeB3108.
This NRTI in phase II study. In vitro data presented at the XIII International AIDS Conference indicate the drug has activity against HIV variants resistant to other NRTIs, namely zidovudine and lamivudine. Clinical data on treatment experienced patients showed DAPD producing a maximum median decline in viral load of 1.1 log after 15 days of monotherapy. The drug was dosed at 500 mg twice daily and was well tolerated. DAPD has no food effect. Abstract TuPpA1146.
Arguably the most promising new agent in development, T-20 will soon enter phase III study. An inhibitor of HIV fusion, the drug's mechanism of action is novel. In a trial of highly experienced patients presented at the XIII International AIDS Conference, the mean decrease in viral load was 1.5 log after 48 weeks of study. Thirty-nine percent achieved HIV RNA levels below 400 copies/mL. This is a remarkable magnitude and duration of response for a heavily pretreated population. Unfortunately, as a synthetic peptide, T-20 cannot be taken orally and is instead administered by subcutaneous injection. Skin nodules formed at the site of injection in most of the patients taking T-20, but the drug was otherwise well tolerated. There is presently no expanded access program for the drug, and it probably will not reach market until 2002. Abstract LBPp116.
Acyclovir Protection Against AIDS-Related Lymphoma?
High doses of acyclovir given for a year may help decrease the risk of AIDS-related non-Hodgkin's lymphoma (NHL). Ignatius Fong, MD, of the University of Toronto and colleagues studied 29 AIDS patients with NHL and 58 control subjects matched for age, sex and AIDS duration. The study showed that 46.6% of control subjects had taken acyclovir at daily doses of 800 mg or more for a year, compared to 6.9% of the NHL patients. Also, 72.4% of patients with NHL and 32.8% of the control subjects had never taken acyclovir prior to developing lymphoma. The research, published in Clinical Infectious Diseases (30:5, p. 757, 2000), indicates that high-dose acyclovir or ganciclovir/foscarnet given for at least 12 months is linked to protection against AIDS-related NHL.
Interleukin 2 Plus Antiretroviral Therapy
Adding interleukin 2 (IL-2) to combination antiretroviral therapy boosted CD4 T cell counts 112% in HIV-infected patients, compared with an increase of 18% in similar patients taking combination therapy alone. Also, the mean CD4 T cell percentage was increased from 20.4% to 32.3% in the group receiving IL-2 (37 patients), compared with 20.4% to 23.0% in the group receiving antiretroviral therapy alone (41 patients). In addition, 67% of the patients receiving IL-2 had viral load levels below 50 copies/mL compared to 36% in the other arm. The researchers reported that the effect of IL-2 was dose dependent. The study was published in The Journal of the American Medical Association (284:2, p. 183, 2000). Patients receiving IL-2 were given 6 cycles of therapy, once every 8 weeks. Each cycle of IL-2 was administered at a starting dose of 7.5 million International Units (IU) every 12 hours for 5 days. Over 50% of those receiving IL-2 experienced grade 3 adverse events including asthenia (weakness), fever, arthralgia (pain in the joints), myalgia (muscle pain) and increased levels of bilirubin, alanine aminotransferase and aspartate aminotransferase. The clinical benefits of the addition of IL-2 to antiretroviral therapy have yet to be evaluated.
This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.