Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
How adherent does a patient have to be to maintain virologic suppression with protease inhibitors? In a study of 84 patients where adherence was monitored electronically with the use of a device called MEMScap, the association at three months between adherence and suppression was found to be highly significant. Of the patients who had an adherence rate of greater than 95% a total of 81% remained virologically suppressed. When adherence dropped to between 95 and 90% the rate of virological suppression dropped to 64%. Only 50% of the patients who took their medications 80 to 90% of the time remained suppressed. With 70 to 80% adherence only 25% of patients remained suppressed and with less than 70% adherence only 6% remained virologically suppressed. Mean adherence with regimens taken twice a day was 73% and for those taken three times a day it was 71%. Poor adherence was associated with active depression, active alcoholism, African-American race, lower educational level and higher viral load (Abstract 92).
A study conducted from September to December 1997 interviewed subjects regarding antiretroviral medications. It found that over one third of those interviewed were not receiving any form of highly active antiretroviral therapy (HAART). The subjects included 2248 persons with less than 500 CD4 T cells and viral loads of greater than 10,000 copies or with HIV disease symptoms. Men took HAART more often than women (68% versus 55%); whites took it at a rate of 71%, Hispanics at a rate of 67% and African-Americans at a rate of 55%. Factors associated with greater use of HAART included more education, private insurance and attitudes regarding the effectiveness of antiretroviral therapies at prolonging and improving quality of life (Abstract 105).
Scientists from the University of Washington and the Fred Hutchinson Cancer Research Center reported 37 individuals who remain seronegative despite repeated high-risk sexual activity with their HIV-infected partners. These individuals have been followed since 1996. Complete HIV genome sequences have not been identified in the blood of these persons, but sequences from the env, gag and pol genes of HIV have been detected in resting cells of these individuals. These individuals showed no replication or very low replication of HIV, no overt systemic infection and a consistent strain which indicates that they were not reinfected with other strains of HIV despite the continued high-risk sexual exposure (Abstract 8).
French researchers reported on the safety and efficacy of lamivudine (Epivir) and zidovudine (Retrovir) for the prevention of vertical transmission. Lamivudine was given at 150 mg twice a day from 32 weeks until labor and to the child at 2 mg/kg twice a day for 6 weeks. Zidovudine was given according to the Pediatric AIDS Clinical Trials Group 076 study recommendations. The mother to child transmission rate was 2.6% in the lamivudine/zidovudine group and 6.5% in a comparator zidovudine monotherapy group. Resistance to lamivudine was reported in 53 of 132 women (Abstract 267). The researchers reported separately from the abstract that two infants had died in the first year of life in the lamivudine/zidovudine portion of the study. The deaths were attributed to a rare neurological disorder associated with mitochondrial dysfunction (Abstract 267).
A late-breaker presentation reported data from an amprenavir (Agenerase) study showing that protease inhibitor mutations of HIV can appear in semen even before the virus rebounds in the plasma (Abstract LB11). Another abstract discussed the correlation between HIV in the semen and the plasma, concluding that there is a direct correlation. Seminal plasma HIV viral load levels are on average one log lower than blood plasma HIV viral load. Treatment with antiretrovirals rendered the viral load in the semen undetectable but HIV could be cultured equally from treated and untreated patients. Presumably being undetectable does not preclude the possibility of infecting another person (Abstract 220). It seems it is too soon to throw away those condoms.
In a study by Merck Research Laboratories comparing indinavir (Crixivan)/zidovudine/lamivudine versus efavirenz (Sustiva)/zidovudine/ lamivudine a subset of patients who experienced virologic rebound during the first six months of treatment were analyzed. Of these failing patients over 75% expressed resistance associated with reverse transcriptase (i.e., resistance related to zidovudine, lamivudine or efavirenz) and less than 25% expressed resistance associated with protease (i.e., indinavir). The results, the researchers claim, show that patients need not change all drugs in a failing regimen, but rather that they should replace only the drugs that have failed and attempt to intensify the regimen (Abstract 492). These findings contradict prior thought that the strongest drug in a combination regimen is generally the first to fail.
Resistance to drugs has been shown to exist even before the patient has taken any form of therapy. In a late breaker abstract researchers analyzed the plasma from 114 drug naïve participants with documented infection within the last three years. The overall prevalence of a significant mutation was 21%. This high a prevalence of mutation suggests resistance testing prior to implementation of the initial regimen may be useful (Abstract LB9). In a separate analysis resistance testing was done on blood plasma samples of 69 subjects from 5 cities (San Diego, Los Angeles, Dallas, Denver and Boston). The percentage of subjects with reduced susceptibility to nucleoside analogs was 3%; to non-nucleosides analogs 17%; and to protease inhibitors it was 13%. Overall reduced susceptibility to one or more drugs occurred in 28% of the study population (Abstract LB9).
The question of whether men and women have a different course of HIV disease has been asked frequently. Scientists at Johns Hopkins University compared viral load levels in two large groups. The first group included 1511 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS). The second group included 1262 antiretroviral naïve women enrolled in the Women's Interagency HIV Study. In comparing the two groups adjustments were made for CD4 T cell count, age, clinical symptoms and injection drug use. Women with CD4 T cell counts above 500 cells had viral loads that were 24% lower than the viral load of men at this same level. Women with CD4 T cell counts of between 200 and 500 cells had viral loads that were 40% lower. When CD4 T cell counts fell below 200 cell the viral loads tended to be the same. The results of this study suggest that the threshold for initiating treatment for women may be different than it is for men (Abstract 274).
Scientists from the University of Washington Medical School have determined there is a correlation between the elevated production of myostatin and wasting in HIV. Myostatin is a growth and differentiation factor that is part of the tumor factor beta superfamily. The researchers compared myostatin levels in men with asymptomatic infection, men with AIDS-associated wasting and six HIV-uninfected men. The men with wasting had the highest levels of myostatin and the uninfected men had the lowest levels of this factor. There was a correlation between higher viral load and greater expression of myostatin and lower protein synthesis. In addition it was noted that a mouse genetically engineered not to express the myostatin gene grows muscles that are two to three times larger than normal (Abstract 242).
Data from the MACS cohort continue to provide information regarding the natural history of HIV disease. In this latest analysis the rate of progression to AIDS was associated with the so-called "set point" and the rate of increase of the viral load over three years. The viral set point is the viral equilibrium reached after acute seroconversion. After initial infection the viral load goes up dramatically then is brought down by the body's immune system and finally settles at a level at which it remains until disease progression. Different people have different set points. Previously, scientists had determined that the higher the set point the greater the chance of progression. This study correlates progression not only with set point but also with the rate of viral load increase over three years. Subjects closest to time to AIDS had the steepest increases in viral load over the three-year period preceding AIDS (Abstract 273).
It is well established that for HIV to infect a cell it must attach to the CD4 molecule on the surface of the cell and it must bind to one of two co-receptors: CXCR4 or CCR5. Scientists in Spain studied the question of whether the expression of the co-receptors varied with disease progression and with therapy. Subjects were all antiretroviral naïve and were divided into three groups. The first group consisted of early stage patients with greater than 500 CD4 T cells and viral loads of less than 10,000. The second group consisted of advanced stage patients with less than 200 CD4 T cells and viral loads of greater than 50,000. The final group was a control group of HIV-uninfected healthy subjects. The advanced group was given therapy with lamivudine, stavudine (Zerit) and indinavir. Flow cytometry tests showed CCR5 expression was significantly increased in the advanced stage group as compared to the control group, but was close to normal in the early stage group. CXCR4 expression was increased in both the early and advanced stage groups. After treatment the advanced group showed a significant decrease in expression of both CCR5 and CXCR4 co-receptors.
Patients treated with protease inhibitors often have a rebound in viral load associated with the development of resistance to the treating agent. At times viral load goes up but CD4 T cells do not go down. Scientists from the Gladstone Institute of Virology and Immunology are asserting that protease inhibitor-resistant HIV may be impaired in its ability to replicate. In an experiment scientists were able to show that untreated HIV was capable of replicating at a high rate and depleting CD4 T cells in the thymuses of mice. HIV that mutated to become resistant to protease inhibitors, however, replicated at a much slower rate and caused no CD4 T cell depletion. The scientists assert that this may account for the slower disease progression of some patients living with protease inhibitor-resistant HIV (Abstract 4).
Some patients fail protease inhibitor therapy and their viral loads increase. Despite this virologic failure many are able to maintain the increases in CD4 T cell counts achieved with the therapy. This disconnect between viral load and CD4 T cell count was studied by researchers using assays that check for fitness of the virus. Despite the fact that the mutated virus showed phenotypic resistance the fitness assay showed a loss of fitness of 27.5%. This loss of fitness was strongly correlated with protease inhibitor resistance but not with viral load levels (Abstract 331).
The rise in CD4 T cells seen with protease inhibitor therapy has generally been attributed to the profound viral suppression produced with these drugs, allowing the increased survival of newly produced cells or their redistribution from other compartments. Scientists from the University of Ottawa have conducted a test tube experiment that indicates protease inhibitors themselves may be in part responsible for the survival of some CD4 T cells. Cells were placed in the test tube with either reverse transcriptase inhibitors or protease inhibitors and monitored for a phenomenon called "apoptosis," or programmed cell death. Apoptosis occurs naturally in the immune system but is accelerated with HIV, accounting for some of the abnormal depletion of CD4 T cells. The scientists found that apoptosis was inhibited by protease inhibitors but not with reverse transcriptase inhibitors. The scientists believe this direct effect of protease inhibitors on survival may account for their therapeutic superiority (Abstract 349).
A study by researchers at the University of California in San Francisco analyzed the incidence of oral lesions from 1990 to 1998 and correlated these with CD4 T cell counts and antiretroviral therapy. Researchers noted an overall decline in common lesions such as hairy leukoplakia and oral candidiasis. However, there was a dramatic increase in the incidence of oral warts with the use of protease inhibitors (Abstract 704).
Researchers from the University of Alabama reported the birth of an HIV-infected child with a strain of the virus that appears to be resistant to multiple reverse transcriptase and protease inhibitors. The child had received zidovudine from birth and the mutations were detected in the first blood specimen, which was obtained at 24 days after birth. The mother had received various reverse transcriptase and protease inhibitors sequentially, as monotherapy and in combination. In addition, the mother's viral suppression was incomplete and had risen above 500 copies on at least 6 occasions. Finally, it was noted that maternal membranes had ruptured 12 hours before delivery, a contributing factor to increased risk of vertical transmission. The infant's therapy was changed to stavudine, lamivudine and nelfinavir (Viracept). A subsequent genotypic analysis showed all the same mutations with the addition of the M184V mutation responsible for resistance to lamivudine (Abstract 266).
Robert Murphy, MD, presented data from a study of ABT-378, a protease inhibitor (PI) under development by Abbott Laboratories. The study examined three doses of the drug, all combined with small amounts of ritonavir (Norvir), plus lamivudine and stavudine. After six months of treatment, viral load was rendered undetectable (less than 400 copies) in approximately 95% of the subjects by on-treatment analysis. Side effects included diarrhea and triglyceride elevations; however, no subject discontinued study for a drug-related reason. The Coalition for Salvage Therapy, an ad hoc group of treatment activists, believes ABT-378 may be effective against PI-resistant virus, and has put pressure on Abbott to make the drug widely available through expanded access. So far, the company has balked, saying it wishes to study the drug further. Abbott expects to file a new drug application for ABT-378 in mid 2000.
The side effects and inconvenience of protease inhibitor therapy have sparked interest in PI-sparing regimens. Christina Katlama, MD, presented data on the Atlantic study, which examines the safety and effectiveness of two such regimens. Study participants received indinavir, a protease inhibitor, or nevirapine (Viramune), a non-nucleoside reverse transcriptase inhibitor, or lamivudine. In addition to one of these drugs, all participants also received stavudine and didanosine (Videx). After six months of treatment, 71% of the subjects in the indinavir-containing arm of the study had viral loads of less than 50 copies by on treatment analysis. In the nevirapine-containing arm, the viral load was less than 50 copies in 67% of the subjects. In the lamivudine-containing arm, only 56% of the volunteers saw their viral load fall below 50 copies. In this study, nevirapine—at least in combination with stavudine and didanosine—provided viral load suppression not statistically different from that of indinavir. Supporters of PI-sparing therapy— not to mention Roxanne Laboratories, which makes nevirapine—should find the results of this study encouraging.
Data presented by DuPont Pharmaceuticals continue to suggest that efavirenz is one of—if not the—most potent antiretroviral on the market. In DuPont 006, investigators assigned 450 subjects, most treatment naïve, to one of three arms:
After 48 weeks of treatment, 98% of the subjects in the first arm had viral loads of less than 400 copies by on treatment analysis. In the second group, 86% percent of the volunteers were undetectable; in the third, 84%. This study is open-label and therefore not as scientifically rigorous as a double-blind trial. Moreover, an unusual number of participants dropped out of the three drug indinavir-containing arm, which may reflect—at least in part—bias on the part of DuPont-sponsored investigators. Still, these data provide further support for PI-sparing treatment, and suggest that efavirenz offers robust anti-HIV activity for patients not previously exposed to therapy.
Indinavir and ritonavir are both powerful protease inhibitors; however, indinavir requires adherence to a strict, three times daily dosing schedule and ritonavir is probably the most poorly tolerated drug in its class. Both agents have lost traction in the market to the widely popular—if not especially potent—nelfinavir. In a twist of irony, investigators presented data on the blending of indinavir and ritonavir, a combination that may make both drugs more tolerable while further enhancing their efficacy. Researchers at Merck dosed healthy volunteers with various combinations of ritonavir and indinavir. When used alone at 800 mg every eight hours, indinavir has a poor pharmacokinetic profile; patients must also take it on an empty stomach. But when combined with ritonavir, indinavir trough levels improve dramatically even when the drugs are given with food. Cassy Workman of Australia has used this combination for salvage therapy in heavily treated patients and obtained promising results. It's a combination that may also salvage market share for Merck and Abbott, makers of indinavir and ritonavir, respectively.
Drug resistance tests are expensive. Are they worth it? Investigators presented data from the Genotypic Antiretroviral Resistance Testing (GART) study, which compared genotypic resistance testing plus "expert advice" to no testing and no advice. The one hundred fifty-three patients in this trial had experienced virologic breakthrough on a protease inhibitor and were in search of second-line therapy. Eight weeks into the study, the median viral load decrease for subjects receiving genotypic testing and expert advice about therapy was 1.17 log. For subjects in the control group, who received neither testing or advice, the median viral load drop was only 0.62 log. By week 12, however, the difference in viral load suppression between groups was starting to fade, which suggests that the benefits of genotypic-based therapeutic decision making may be limited.
For the last few years, scientists have engaged in intense debate about the way HIV causes CD4 cell loss. One group, for whom David Ho, MD, is chief spokesman, argues that the virus is destroying T cells. Another group, led by Giuseppe Pantaleo, MD, insists that HIV is mostly inhibiting the production of new cells. Mike McCune, MD, presented findings in support of the second view. Using a new laboratory technique that identifies recently produced cells, McCune and his colleagues demonstrated that CD4 cell production increases following the initiation of highly active antiretroviral therapy. If Ho's model of T cell loss was right, treatment should produce a decrease in T cell destruction, not an increase in production (See RITA!, 5:1, p.5, 1999.).
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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