Baseline Viral Load May Affect Time to Treatment Success

An analysis of HIV-infected individuals enrolled in study DuPont 006 revealed some interesting trends with regard to time needed to achieve viral suppression (defined as a viral load of less than 50 copies/mL). Baseline plasma viral load was a significant predictor of early (within 24 weeks) versus late response to antiretroviral therapy. Some individuals with baseline viral loads greater than 100,000 copies/mL needed at least 36 weeks to achieve viral loads less than 50 copies/mL. The authors note that current treatment guidelines (including those of the International AIDS Society-USA, the U.S. Department of Health and Human Services, and the British HIV Association) set 4-6 months (16 to 24 weeks) as the time when a new treatment regimen should lower a patient's viral load to less than 50 copies/mL. The authors suggest that individuals with baseline viral loads greater than 100,000 copies/mL may need up to 36 weeks to achieve viral loads less than 50 copies/mL. Abstract 547.

Interactions Between Kaletra and Atorvastatin, Pravastatin

Scientists at Abbott Laboratories reported on the interaction between certain lipid-lowering agents and lopinavir/ritonavir (Kaletra). In a study involving 12 healthy volunteers, participants were divided into two groups, with one group given the combination of lopinavir/ritonavir and atorvastatin (Lipitor). The other group was given the combination of lopinavir/ritonavir and pravastatin (Pravachol). Pharmacokinetic studies concluded that the levels of pravastatin were only slightly increased and did not warrant adjusting the dosage of pravastatin. However, the levels of atorvastatin were substantially increased when combined with lopinavir/ritonavir. The researchers recommended careful monitoring for adverse events and laboratory abnormalities when co-administering these drugs. This was particularly true if the dose of atorvastatin was greater than 10mg daily. No effect was seen on the levels of lopinavir/ritonavir. Abstract 1644.

Rhabdomyolysis: A New Word for the HAART Vocabulary?

Researchers from The University of Texas Southwestern Medical Center in Dallas reported what appear to be the first cases of a metabolic disorder called rhabdomyolysis resulting from a drug interaction between protease inhibitors and certain statins. Rhabdomyolysis is a disorder resulting in muscle damage that can lead to life-threatening kidney failure. It is generally associated with, among other things, severe exertion (such as marathon running or calisthenics), seizures, trauma, use or overdose of drugs such as cocaine, amphetamines or heroin, or with alcoholism. Rhabdomyolysis has also been associated with the use of lipid-lowering agents with other drugs that inhibit the metabolic pathways of these drugs. Researchers reported rhabdomyolysis in two patients taking a combination of statins and protease inhibitors. In the first case, the patient was taking indinavir (Crixivan), ritonavir (Norvir), zidovudine/lamivudine (Combivir) and 40mg daily of simvastatin (Zocor). Due to patient error, the amount of indinavir was not reduced when adding the ritonavir. Thus, the patient was taking a full dose of indinavir (800mg three times a day) with ritonavir (400mg twice daily). The patient presented with dark urine and lower extremity weakness and pain causing an inability to walk. Laboratory tests were consistent with rhabdomyolysis, hepatitis and acute renal failure. The patient stopped all medications and required hemodialysis. After the patient's laboratory tests returned to normal, the patient was able to resume HAART without the simvastatin. The second case involved a patient taking stavudine (Zerit), lamivudine (Epivir), indinavir and 10mg daily of atorvastatin. The researchers caution against the use of statins and protease inhibitors that compete for the same metabolic pathways. Abstract 1297.

"Baby Dose" Ritonavir Could Breed Resistance

Investigators in Nice, France, looked at the possibility of whether or not the use of low-dose ritonavir (Norvir) as a pharmacokinetic booster of other protease inhibitors might breed viral mutations specific to ritonavir. They examined 34 patients in the VIRADAPT study who were treated with ritonavir (100mg twice daily) and soft gel saquinavir (600mg three times daily) as part of a rescue (salvage) regimen. At baseline, 26.4% and 11.7% of these individuals had mutations associated with ritonavir resistance, at positions 82 and 46 respectively. In those individuals without ritonavir specific mutations at baseline, 23.0% and 14.7% developed the mutations at positions 82 and 46 respectively. The authors note that treatment-naive patients could be at particular risk for developing mutations specific to ritonavir. They suggest the use of "baby dose" ritonavir only with protease inhibitors sharing the same mutations as ritonavir, and with patients who already have ritonavir-specific mutations. Abstract 1267.

Benefits of Stable Viremia?

Researchers from Rush Medical College in Chicago and the University of Colorado in Denver presented data on HIV-infected patients on antiretroviral therapy with viral loads between 50 and 10,000 copies/mL for more than six months. Twenty-five such patients, called plateau patients (P), were compared to 12 patients on failing regimens (F) with viral loads greater than 10,000 copies/mL for more than six months, and also compared to 10 patients with undetectable viral loads (U) for more than six months. At three years follow-up, absolute CD4 T cell counts were significantly higher in the U and P groups, compared to the F group. However, the change in CD4 T cell count per year was significantly higher in the U group, but not P or F (which did not differ significantly from each other). Lymphoproliferative responses were found in 32% of P and 50% of U, but in 0% of F patients. Duration of HIV disease and antiretroviral therapy did not differ between those with and without such responses, but viral load was lower and nadir CD4 counts tended to be higher. In addition, the P group had fewer mutations for reverse transcriptase and protease genes, as well as a decreased rate of accumulation of these mutations. The researchers speculate that these various factors may lead to the establishment of a new virus-host set point that may prove clinically beneficial in patients like those in group P. Abstract 565.

Immune System Activation

One of the most intriguing aspects of HIV disease is the role that immune system activation can play in progression. Intuitively, one expects immune system activation to control pathogens. However, prior studies have shown that chronic activation of CD8 T cells is associated with CD4 T cell loss. How are activated CD8 cells identified? Primarily they are classified as activated when the CD38 molecule appears on their surface. Now scientists have taken this marker further and identified cells that have many of these CD38 molecules (greater than 5000 CD38 molecules per cell). These cells are being called CD8/CD38++ cells to denote the fact that they are not just activated but highly activated CD8 cells. One hundred and thirty-eight patients treated during primary infection with the quadruple antiviral regimen of zidovudine (Retrovir), lamivudine (Epivir), abacavir (Ziagen) and amprenavir (Agenerase) were compared to two control groups of 20 uninfected subjects and 25 infected but untreated subjects. The number of CD8 cells and CD8/CD38++ cells were measured in the three groups. In the uninfected patients the median CD8/CD38++ cells were 11 cells/mm³. In the infected but untreated group, the median CD8/CD38++ cells were 316 cells/mm³. In the patients treated during primary infection the median CD8/CD38++ cells prior to treatment was 479 cells/mm³. This level declined exponentially for the first four weeks of treatment and then linearly until reaching a median of 40 cells/mm³ at 28 weeks. What is the significance of this study? It shows that treatment during primary infection can lower activation to near normal levels. Further, since the study was able to correlate levels of viral suppression with the levels of CD8/CD38++ expression, the researchers speculate that this activation assay may be useful as a surrogate measure for early viral replication (presumably even before it can be measured by standard viral load tests), when antiviral therapy is stopped or interrupted. Abstract 806.

Early or Delayed HAART?

The question of when is the best time to initiate highly active antiviral therapy (HAART) is still an intensely debated one. Researchers from The University of Washington in Seattle presented data on two groups of patients who started HAART either early in infection or delayed it until later. For purposes of the study early initiation was defined as within 120 days of infection (median 51 days) and delayed initiation was defined as more than 120 days after infection (median 793 days). In this study 15 patients had initiated HAART early and 30 patients had delayed the initiation of HAART according to the set parameters. At the end of two years the early HAART group had better absolute CD4 T cell counts and CD4 T cell percentages. However, the gains in CD4 T cells and percentage achieved by the delayed HAART group were similar to those of the early HAART group once the delayed group began therapy. When the groups were examined for viral rebound (viral load greater than 500 copies/mL), none of the early HAART patients rebounded, whereas eight in the delayed HAART group had viral rebounds. This apparent advantage for the early HAART group was nullified when it was noted that many in the delayed group had started on dual therapy or monotherapy prior to going on HAART. When the analysis was limited to patients in the delayed group who went directly on HAART without first doing dual therapy or monotherapy versus the early group, there was no statistical difference between the two groups: only two in the delayed group had viral rebound compared to none in the early group. Abstract 808.

Are Treatment Interruptions Safe?

Michael Saag, M.D., and colleagues at the University of Alabama at Birmingham reported on a review of viral loads, CD4 T cell counts and clinical outcomes of patients who interrupted therapy. The patients were part of an ongoing observational study. In order to be included in the analysis, patients must have interrupted therapy for at least 30 days and been back on therapy for at least 30 days. A total of 78 patients were eligible for analysis. The median length of follow-up was 173 days. Seventy-two percent of patients achieved viral load outcomes that were less than or equal to their levels prior to interruption. Fifty-nine percent of patients achieved CD4 T cell levels of greater than 90% of their levels prior to interruption. Only 10% of patients achieved CD4 T cell levels less than 50% of pre-interruption levels. No predictors of response were identified in this analysis. Abstract L-18.

Combine Study Update

Thirty-six-week data from the Combine Study was presented by researchers from Spain and Argentina. The randomized, open-label study compares the administration of zidovudine/lamivudine (Combivir) with either nelfinavir (Viracept) or nevirapine (Viramune) twice daily in 142 HIV-infected, treatment-naive patients. The two groups were similar, although the nelfinavir group had a greater number of women than the nevirapine group. Baseline CD4 T cell count was 359 cells/mm³ and mean viral load was greater than 125,000 copies/mL. Intent-to-treat analyses (missing patients counted as failures) revealed that 55.7% of patients in the nelfinavir arm achieved viral loads less than 200 copies/mL, compared to 70.8% of patients in the nevirapine arm (p=0.06). Likewise 38.6% of patients in the nelfinavir arm achieved viral loads less than 20 copies/mL, compared to 66.7% of patients in the nevirapine arm (p<0.001). When comparing only patients whose baseline viral loads were above 100,000 copies/mL, 15.4% had viral loads less than 20 copies/mL in the nelfinavir arm compared to 61% in the nevirapine arm. There were no differences in CD4 T cell gains, which were greater than 130 cells/mm³ in both groups. The researchers conclude that the zidovudine/lamivudine/nevirapine regimen "may have greater efficacy" than the zidovudine/lamivudine/nelfinavir regimen. Abstract 694.

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