Gains in HIV Knowledge Reported at 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
No particularly groundbreaking news was presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Toronto in September, but the conference did provide data on issues that have been of interest for some time.
This article focuses on studies of antiretroviral drugs, drug/drug interactions and immune reconstitution with HAART.
Antiretroviral Drug Studies
Numerous studies examining approved and experimental antiretroviral drugs were presented at ICAAC.
The Food and Drug Administration (FDA) approved the new antiretroviral Kaletra (ABT-378/r) just two days before the conference (see report in the November edition of Positive Living).
Kaletra is a combination of lopinavir (ABT-378) and ritonavir. This new protease inhibitor combination takes advantage of a drug/drug interaction, using small amounts of one drug to greatly enhance the blood levels of another drug.
In a multi-center, double-blind study presented by S. Walmsley and colleagues, 653 antiretroviral-naive patients were randomized to receive either ABT-378/r twice daily plus d4t plus 3TC or nelfinavir three times a day plus d4t and 3TC. Twenty-four week results were presented at ICAAC.
Greater suppression of viral load was seen in the ABT-378/r group than in the nelfinavir group. In both groups, side effects occurred at a similar frequency with the most common being diarrhea. However, increased triglycerides occurred in 7 percent of the ABT-378/r group as compared to 1 percent of the nelfinavir group. Treatment discontinuation was similar in both groups.
While this study showed the effectiveness of ABT-378/r as an initial therapy, the results may be biased. The nelfinavir was given three times a day, raising the possibility of decreased adherence in the nelfinavir arm. Additional studies are needed to examine the issue of how adherence affects efficacy.
In another study of the combination of ABT-378/r, d4t and 3TC as initial therapy, C. Benson and colleagues presented a long-term follow-up through 96 weeks. This study indicates that ABT-378/r is comparable to other protease-based regimens in its sustained suppression of HIV.
The most common side effect was diarrhea, occurring in 23 percent of all patients. Additionally elevated lipids (cholesterol and triglycerides) and elevations in AST or ALT were the most common laboratory abnormalities, indicating these values should be monitored in patients receiving this combination.
The combination of ABT-378 and ritonavir allows high blood concentrations that in theory should adequately suppress protease inhibitor resistant virus. This concept was examined in a study by S. Becker and colleagues.
Two different doses of the protease inhibitor combination of ABT-378/r (400/100 [three capsules] twice daily and 533/133 [four capsules] twice daily) were combined with efavirenz (Sustiva) and nucleoside analogues in highly protease inhibitor experienced patients. All patients were NNRTI-naive. After it was discovered that efavirenz lowered the blood levels of ABT-378/r, all patients were switched to the higher dose of ABT-378/r.
Results at 24 weeks show ABT-378/r in combination with efavirenz and nucleoside analogs was effective in suppressing viral load. Although these results in this highly antiretroviral-experienced group were positive, it is difficult to determine if the viral suppression was due to the effect of ABT-378/r or efavirenz since the patients were NNRTI naive.
Two ICAAC studies (Abstracts 1664 and 1663) provided data showing Videx EC, a new extended release formulation of ddI, attained similar blood levels as the chewable tablet.
Videx EC, recently approved by the FDA (see report in this edition of Positive Living) is a form of ddI that is easier to take. Because the initial formulation of Videx (ddI) had to be chewed, some patients found the drug more difficult to take than other nucleoside analogues.
This beaded formulation dissolves in the small intestine instead of the stomach, thus avoiding stomach acid and the need for antacids. Both studies, sponsored by Bristol-Myers Squibb (BMS), makers of ddI, showed the only difference between the new formulation was increased absorption time. Videx EC is taken once a day and must be taken on an empty stomach.
Because the chewable tablet formulation of ddI includes an antacid to aid in absorption, taking ddI with other drugs is a problem. In another study by BMS (Abstract 1629) the new formulation showed no significant interactions with indinavir, ketoconazole or coprofloxaxin. This will allow the co-administration of these drugs.
Sanne and colleagues presented data from a Phase II, randomized study which compares the safety and antiviral activity of BMS-232632, the first experimental protease inhibitor that is dosed once daily, with nelfinavir, alone and in combination with ddI and d4T.
Antiretroviral naive subjects with HIV RNA less than 2,000 c/ml were given one of three dose levels of BMS-232632 (200, 400 or 500 mg) or nelfinavir 750 mg TID both as monotherapy (two weeks) and in combination with ddI and d4T.
At week 24, 30 percent to 80 percent of patients had viral loads below 50 c/ml, with the best results shown for the higher doses. Most common side effects were diarrhea, infection and nausea. The most common laboratory abnormality was hyperbilirubinema. No elevated lipids were reported at week 24.
Additional studies will confirm the effectiveness of this antiretroviral and give additional data on side effects.
Tenofovir, a new nucleotide analogue, is of particular interest since it has a favorable resistance profile active against wild type and resistant HIV. Unlike its cousin adefovir, tenofovir is not associated with any significant renal dysfunction.
In a study by R. Schooley and colleagues, once-daily dosing of Tenofovir DF provided durable antiviral suppression for treatment experienced patients with evidence of nucleoside resistant virus. After 48 weeks, no significant increase in CD4 cells was observed.
Fusion inhibitor T-20 with TAK-779
In the assay, the drugs proved to be non-toxic and showed synergy at various concentrations. Because both drugs inhibit HIV as it enters the cell, combinations of these drugs will be important therapy options for individuals with extended treatment history.
Compact Triple Nucleoside Regimen
This study reinforces that adherence is a crucial factor for therapy success. The abacavir regimen, which consisted of two pills twice a day, showed superior adherence over the more complicated regimen of indinavir which required patients to take four pills in the morning, two pills in the afternoon and then four pills in the evening. About 1 percent of the patients missed three days in a row of the abacavir combination versus 14 percent in the indinavir group.
Drug Interaction Studies
Beneficial and potentially dangerous drug interactions were examined by many researchers presenting data at ICAAC.
In a presentation by Aarnoutse and colleagues, the influence of Sustiva (efavirenz) on a twice-daily regimen of Crixivan (indinavir) 800 mg and Norvir (ritonavir) 100 mg was examined in healthy volunteers. Efavirenz was added to the dual-protease regimen after 14 days and was given for 14 additional days. Pharmacokinetic analysis were done at 14 days and at 28 days.
Researchers found reductions in both indinavir and ritonavir after the addition of efavirenz. The area-under-the-curve (AUC) for indinavir was decreased by 19 percent; the AUC for ritonavir was reduced by 40 percent. No significant change in levels of efavirenz was seen. The author suggested that decreased levels of indinavir may be a result of changes in ritonavir concentrations. Additionally, combining efavirenz with Kaletra (ABT-378/ritonavir) demonstrates reductions in levels of Kaletra.
In another presentation, S.C. Piscitelli discussed how the use of non-nucleosides (efavirenz and nevirapine, in particular) affected the steady-state of ritonavir-combined with other protease inhibitors.
Since ritonavir is used to enhance the blood levels of other protease inhibitors, reductions in ritonavir caused by efavirenz and nevirapine is cause for concern. He noted many studies have been done examining the interactions of two drugs, but patients with HIV rarely if ever take only two drugs. He highlighted the need for further clinical trials to examine how physicians should dose complex combinations of medications.
Lipid-lowering Agents and Protease Inhibitors
Because some antiretroviral agents, especially protease inhibitors, can raise lipid levels, doctors often prescribe lipid-lowering agents known as statins.
Two ICAAC studies examined the interactions between statins and protease inhibitors. In the first study (Abstract 425) nelfinavir was co-administered with either simvastatin or atrovastatin. Results showed potentially dangerous increases in blood levels of both statins (AUC increased 506 percent for simvastatin and increased 71 percent atorvastatin). Thus, simvastatin should not be used with nelfinavir and atorvastatin must be used with extreme caution.
Another study (Abstract 1644) examined the interaction between ABT-378/r and pravastatin (20 mg daily) or atorvastatin (20 mg daily). A five-fold increase in AUC for atorvastatin and a 30-percent increase for pravastatin were observed. This study indicates using caution when administering atrovastatin while pravastatin may be used without a dose reduction.
Previous studies have indicated that treatment with HAART during primary or acute HIV infection may preserve some important immune responses that may be lost if treatment is delayed.
Tenner-Racz and colleagues presented some interesting data at ICAAC on the amount of HIV replication during acute primary HIV infection and how it differed from chronic infection. Fifteen patients with primary HIV infection and eight chronically infected patients were studied. Lymph node biopsies were obtained and analyzed for the amount of free virus and intracellular virus. The samples were also stained to determine the types and numbers of lymphocytes. Additionally, lymph node structure was analyzed.
Results showed that although there was virus present in plasma and blood cells during primary infection, there was little or no virus trapped within the lymph nodes and lymph node structure remained intact unlike chronic infection.
Although this was a small observational study, the results indicate that early intervention with HAART may retain normal lymph node structure and function.
A study by Geise and colleagues looked at the timing of HAART after symptomatic primary infection. Two groups of individuals were treated with HAART, the first group at 120 days after infection (median onset of therapy 42 days) and the second group with delayed HAART (median onset of therapy 789 days). Both groups were treated with HAART for two years and then compared.
A significant increase in the number of virologic failures was seen among those who delayed therapy. No difference was seen in the two groups with respect to AIDS-defining illnesses. Additionally, the group that initiated early therapy experienced significantly higher CD4 counts than those in the delayed treatment group, although the percentage increase in CD4 cells was not altered by delayed therapy.
Lafeuillade and colleagues presented data from an small, ongoing study designed to examine the long-term benefit of antiretroviral therapy including hydroxyurea and IL-2. At the end of the trial the researchers plan to initiate treatment interruptions in selected patients. Of the 12 patients who initiated early therapy, all but one had undetectable viral load (less than 20 c/ml). Analysis of this patient's virus revealed infection with a multidrug-resistant strain of HIV. The researchers also found reduced amounts of virus in the lymph nodes, cerebral spinal fluid and seminal fluid, however, cells within these compartments contained viral DNA.
Chronically-Infected Persons on HAART
In an effort to study how the immune system recuperates over time in chronically-infected individuals, Kaufman and colleagues presented data from a three-year study of 62 men who continue to experience viral loads below 400 c/ml.
Over the three years a trend was seen in the majority of the patients. Steady increases in the number of CD4 cells were seen with the largest increase occurring in the first three months. Additionally CD8 cells, a marker of immune activation, increased during the first three months but then declined steadily over time, though they continued to be slightly elevated in most patients. The researchers proposed that CD8 cells remained elevated due to on-going low level HIV replication.
In a study examining the laboratory immune responses to a specific HAART regimen (amprenavir 1200 mg, abacavir 300 mg and lamivudine 150 mg, all twice a day), Landay and colleagues showed increased thymic mass as well as reductions in markers of immune activation. Unlike other studies, there were no significant increases in CD4 or CD8 cells observed at 24 weeks. Increases in naive CD4 cells were observed however.
Over time, this small group should provide additional information on immune recovery.
The interest in treatment interruptions as a method to teach the immune system to suppress HIV comes from a small number of individuals who were treated during primary HIV infection with HAART and then for various reasons had a series of treatment interruptions. These individuals were able to successfully suppress HIV without further treatment.
A small number of studies have been conducted in chronically infected individuals that have shown occasional reductions in virus replication but the majority of individuals have not had success.
In an interesting study presented by Lori and colleagues, a group of SIV-infected macaques were randomized to receive continuous HAART, HAART followed by a series of short treatment interruptions or receive no treatment at all. The study looked at animals in primary (acute) infection as well as animals with chronic (long-term) infection. The ability of the animals to generate immune responses to SIV was evaluated.
Study results indicate that animals treated with HAART during primary infection, then subjected to treatment interruptions, were able to generate a successful immune response to SIV and fully suppress the virus after the fourth interruption. The chronically-infected animals who were treated with HAART even after successive treatment interruptions were unable to mount a successful immune response to the virus and experienced viral rebound.
Although conducted in an animal model, this research suggests treatment with HAART during primary infection followed by treatment interruptions might be successful in humans.
David Pieribone is associate director of AIDS Project Los Angeles' Education Division. He can be reached by e-mail at dpieribone@APLA.org.
This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.