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CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS The 7th Conference on Retroviruses and Opportunistic Infections was held in San Francisco from January 30 February 2, 2000. This annual conference is sponsored by the Foundation for Retrovirology and Human Health in scientific collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers for Disease Control and Prevention (CDC). This review presents some of the highlights of this conference. For a complete listing of conference abstracts, slides and lectures, see: http://www.retroconference.org/ Using a powerful supercomputer known as NIRVANA, a team of researchers from the Los Alamos National Laboratory in California traced the origin of HIV to 1930, reported Bette Korber, PhD, at the 7th Conference on Retroviruses and Opportunistic Infections. The virus may have originated sometime between 1910 and 1950, but 1930 appears to be the most likely date, based on a complex statistical analysis. Most scientists believe that HIV1, the strain of HIV most prevalent in the US, Europe, and the developed world, evolved from a simian immunodeficiency virus (SIV) in chimpanzees that crossed over to humans. The most popular theory holds that chimpanzees in Africa bit hunters who were pursuing the animals for food. The precise date that a human was first infected with HIV is not known. Hard evidence of the first human infected with HIV is from a blood sample from a man in the Belgian Congo who died in 1959. The new finding from the research team in Los Alamos undermines a theory about the origin of HIV presented by British journalist Edward Hooper in his recent book The River. Hooper says that HIV entered humans when SIV from chimpanzees was used in an experimental polio vaccine tested in the Belgian Congo in the late 1950s. Samples of that vaccine, stored for over 40 years, will soon be tested by several different laboratories to determine whether there is any evidence of a mutated SIV that may be linked to HIV. Gaschen BK, et al. HIV Databases and analysis projects at Los Alamos: An overview. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 164. Several retroviruses appear to have jumped species from primates to humans, according to Dr. Robin Weiss of the UK. The virulence of the virus also changes, becoming either attenuated or strengthened, when such species jumps happen. Weiss R. Our retroviral heritage: Bernard Fields memorial lecture. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract L1. A study by Fischl et al concluded that 100% adherence to treatment leads to higher rates of undetectable viral load in patients compared with patients who take their drugs without supervision. Fortyeight incarcerated patients at the Department of Corrections in Orlando, Florida were enrolled in the study. They received their antiHIV medication by Directly Observed Therapy (DOT), a method of treatment monitoring that also has been used to effectively treat tuberculosis (TB). These patients were compared to 48 other HIVpositive outpatients receiving treatment at the AIDS Clinical Research Unit at the University of Miami, who took their medications on their own using SelfAdministered Therapy (SAT). Using the socalled intenttotreat analysis (all enrolled patients are included in the analysis), the results after 48 weeks revealed that 100% of the DOT incarcerated patients had an undetectable viral load (limit 400 copies per milliliter). Using an ultrasensitive assay of 50 copies per milliliter, 85% had an undetectable viral load. This was significantly greater than the results found with the clinic outpatients, among whom 68% had an undetectable viral load using a test with a lower limit of 400 copies per milliliter and 50% with a limit of 50 copies per milliliter. Fischl M, Impact of directly observed therapy on outcomes in HIV clinical trials. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 71. METABOLIC COMPLICATIONS OF HIV THERAPY PREVALENCE Miro reported that lipodystrophy was seen in 35% of patients treated since HIV seroconversion with combination antiretroviral therapy for up to 2 years. In contrast to some other studies, these data suggest that lipodystrophy syndrome is more an effect of therapy than of duration of HIV infection, at least in this group of patients with only modest immune deficiency. Miro J, et al. Incidence of lipodystrophy in patients with primary HIV1 infection (PHI) treated with HAART. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 12. Risk factors for lipodystrophy included older age, white race, time since first positive HIV test, presence of high triglyceride and cholesterol levels, therapy with the nucleoside analog d4T (stavudine), and therapy with protease inhibitors. These associations, most of which have been seen in earlier studies, remain to be confirmed in prospective studies. The results are confounded further by the fact that since there is still no case definition for lipodystrophy, each investigator defines the syndrome a bit differently. Saves F, et al. Factors related to the presence of fat redistribution in HIVinfected patients treated with protease inhibitor (PI)containing regimens, APROCO Cohort, 1999. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 14 Martinez E. Risk factors for developing lipodystrophy (LD) in patients receiving protease inhibitors. Program and Abstract, of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 15. The HIV Outpatient Study (HOPS) cohort of 1077 patients showed that the likelihood of lipodystrophy increased and was most associated with a patient's age, use of indinavir, and use of stavudine. The presence of lipodystrophy also correlated with loss of body mass index (BMI) and patients with lipodystrophy had significantly more instability of BMI, as measured by range of BMI change Lichtenstein K, Clinical factors related to the severity of fat redistribution in the HIV outpatient study (HOPS). Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 23. GENDER DIFFERENCES AND LIPODYSTROPHY The SALSA study reported very high prevalence rates of lipodystrophy that differed between men and women. Fat accumulation occurred in 84% of males and 97% of females; fat loss in 77% of males and 61% of females. Muurahainen N, et al. Gender differences in HIVassociated adipose redistribution syndrome (HARS): An update. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 26. Changing therapy has gained some acceptance as a means of managing lipodystrophy. Most studies presented to date have shown that switching from a protease inhibitor to a nonnucleoside drug maintains viral suppression in patients who are already suppressed, with varying impact on CD4 cell count. The role of durg switch to reverse symptoms, however, is not as clear. Carr and Cooper reported on a switch study in which patients were randomized to switch PI to a regimen of abacavir, adefovir, nevirapine, and hydroxyurea for 6 months. The results showed a fall in both central and peripheral fat in the switch group. However, therapy also led to a fall in body weight by almost 6 pounds. It is uncertain whether the fall in central fat accumulation is related to the switch in antiretroviral agents or to weight loss per se. It also is unclear whether the loss of central fat represents a loss of visceral fat or a loss of truncal subcutaneous fat. While it is known that visceral fat varies with total fat under normal circumstances, there are no published normative data or other means to correct for changes in visceral fat content due to changes in total fat. Another potential confounding aspect of the study is that abacavir is an NRTI and could have the same effect as hypothesized for d4T. Carr A, Cooper DA. A randomized, multicenter study of protease inhibitor (PI) substitution in aviremic patients with antiretroviral (ARV) lipodystrophy syndrome. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 205. Fetter and colleagues evaluated data in almost 500 individuals taking part in a study comparing amprenavir with indinavir (PROAB3006) to examine the relationship between lipodystrophy and different PIs. This was a randomized comparison of the 2 PIs given with various combinations of NRTIs for a median of about 1 year. Significant differences were found in the reports of altered morphology, with fewer cases in patients taking amprenavir (3% vs 11%). There were more cases with retinoidlike symptoms, eg, hair or nail changes, in the indinavircontaining regimens. These results show that differences in the incidence of morphologic changes may be found between protease inhibitors. Fetter A, et al. Fat distribution and retinoidlike symptoms are infrequent in NRTIexperienced subjects treated with amprenavir. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 18. The shortterm risk of coronary heart disease was not increased by protease inhibitor use according to data from Kaiser Permanente study. Klein et Al reported on 4500 HIV positive patients. Hospitalization rates for coronary artery disease were the same in HIV patients taking protease inhibitors versus those who were not on PIcontaining regimens (5.5 per 1000 person years versus 5.7 per 1000 person years, respectively). Klein D, Do protease inhibitors increase the risk for coronary heart disease among hivpositive patients? Additional followup. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 33. Lactic acidosis is a rare, but severe, often fatal, complication of antiretroviral therapy. The presumed mechanism of action involves mitochonidral toxicity or dysfunction secondary to the nuclesoide RTI group of antiretrovirals. A crosssectional analysis of 1598 patients participating in the Swiss HIV Cohort Study found that serum lactic acid was elevated in 107 patients (10.8%) during a 30day period in August 1999. Most hyperlactatemia, however, was mild, with only 14 patients (0.9%) having a lactate level greater than two times the upper limit of normal. D4T and/or ddIcontaining regimens were associated with a significantly greater risk of elevated lactate (odds ratio 6.6:2.4). Clinical disorders associated with elevated lactate in a multivariate analysis included lipoatrophy and moderate lipodystrophy. Furrer H, et al. Hyperlactatemia and Antiretroviral Therapy in the Swiss HIV Cohort Study (SHCS). Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 57. IMMUNE RECONSTITUTION AND STRUCTURED TREATMENT INTERRUPTION (STI) The concept of Structured Treatment Interruption (STI) has received considerable attention and debate in the past year as a way to enhance immune recovery in patients with HIV. There were several reports at this conference on STI that showed varying results. The basis for the STI strategy is that with effective HAART, HIVspecific cellmediated immunity may actually decrease due to the lack of exposure to HIV antigen. With STI, HIV antigen is provided by autologous virus, which stimulates HIVspecific Thelper and cytotoxic Tlymphocyte (CTL) responses in HAARTtreated patients who have recovered some of their naive T cells. This approach may be useful in acute primary HIV infection after HAART therapy, where the patient may already have the immune capability to respond to exogenous antigens, and in the chronic HIV setting after some degree of immune reconstitution with HAART. STI may also be useful in patients with multidrugresistant HIV, where stopping therapy may allow emergence of wildtype virus and permit use of recycled antiretroviral drugs to suppress virus replication. Several posters presented the experience of a number of investigators with this approach Lori et al from the University of Rome, Italy, tested the hypothesis that the presence of HIVspecific immune response can control HIV during treatment interruption for 8 weeks. Using their cohort of patients treated with didanosine and hydroxyurea, they selected a matched cohort of protease inhibitor (PI)treated patients. Patients treated with didanosine + hydroxyurea were less likely to be fully virologically controlled (1/9 with RNA <50 copies/mL) vs 7/8 of the PItreated patients. Upon stopping therapy, viral rebound to >10,000 copies/mL and/or a CD4+ count decline to <200 cells/mm3 occurred in 5/8 HAART patients by week 6, whereas among the didanosine + hydroxyurea patients, none met these criteria during the entire 8week followup. Average change in viremia was +2.25 log in the HAART patients and +0.27 log in the didanosine + hydroxyurea patients. The CD4+ cell counts decreased and CD8+ cell counts increased to a greater degree in the HAARTtreated patients than in the didanosine + hydroxyurea patients upon treatment interruption. The authors concluded that the reconstitution of HIVspecific immunity seen with treatment of chronically infected patients with the less suppressive didanosine + hydroxyurea regimen was associated with better control of viral rebound during treatment interruption compared with more fully suppressive HAART regimens. Two other studies suggested that STI may not be effective in either controlling HIV replication or in inducing adequate HIVspecific immunity. Carcelain et al from the Hôpital PitiéSalpetrière in Paris studied 3 effectively HAARTtreated patients who underwent 3 to 4 STIs with intensive immunology and virology along with a control group of 5 patients who rebounded while receiving HAART. They reported no significant CD4+ and only weak CD8+ Tcell responses to HIV after drug interruption. Increases in interferongammaproducing CD4+ cells were seen after each treatment interruption; however, these cells were rapidly depleted when viral replication was restored. No expansion of memory CD8+ cells was seen with viral rebound, and therefore little immune control of viral relapse was seen. What conclusions can be drawn from these conflicting results? First, STI may be beneficial for some patients, but until we are better able to identify and monitor these patients, it appears that STI does not provide autovaccination for all. Secondly, treatment interruptions or drug holidays will be a part of HIV care for some patients. In the absence of any selection criteria to identify patients who might benefit from STI, it is important to do what STI says in its name; structure it. This structure must include developing a plan prior to stopping drugs that outlines the monitoring schedule for CD4 and viral load, decides at what level treatment will be resumed, and what the regimen will be when treatment is resumed. Lori F, Foli A, Maserati R, et al. Control of viremia after treatment interruption. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 352. Carcelain G, Tubiana R, Mollet L, et al. Intermittent interruptions of antiretroviral therapy in chronically HIVinfected patients do not induce immune control of HIV. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 356. THE ROLE OF THERAPEUTIC VACCINE Evidence of benefits from an experimental therapeutic HIV/AIDS vaccine was reported by Jin et al from the Aaron Diamond AIDS Research Center in New York City. Four HIVpositive patients were treated with HAART within a median of 60 days after primary HIV infection. The HAART regimen included Crixivan (indinavir) plus Retrovir (zidovudine, AZT, ZDV) and Epivir (lamivudine, 3TC). Prior to starting HAART, the median baseline HIV viral load was 4.8 log copies per milliliter. HIV became undetectable (limit 50 copies per milliliter) and remained so for approximately 2+ years. Then an experimental HIV/AIDS therapeutic vaccine was started. The vaccine included the recombinant (made in the laboratory) ALVAC1452 canarypox virus vaccine and a recombinant gp160 (glycoprotein on HIV's surface, rgp160) vaccine as two components. HIV rebound was delayed in two of the four patients. The first patient did not have detectable RNA until 68 days after HAART was stopped. This corresponded to an initial doubling time of 4 days. The second patients with delayed rebound had detectable virus 85 days after HAART was stopped, with an initial doubling time of 3.2 days. On the other hand, patients three and four had doubling times of 13 and 23 days, which is more typical of what occurs after HAART is stopped in unvaccinated patients who have previously had an undetectable viral load with HAART. Both of these patients had an initial doubling time of 1.4 days, even faster than the average of historical controls (2.4 days). The same authors also reported during their Late Breaker presentation that the two patients with delayed viral rebound had been off HAART for four and eight months, respectively. Their viral loads are 3.8 and 2.5 log copies per milliliter, respectively. These two viral load levels were lower than their preHAART levels. On the other hand, the two patients with an average time to rebound had viral loads of 3.6 and greater than 4.7, respectively, four months after stopping HAART. These results suggest that the delayed rebounder patients had developed a lower viral load setpoint (where the viral load levels off). However, this does not mean that they will retain those levels for a more extended period of time. Jin X, and others. Safety and immunogenicity study on vCP1452/gp160 vaccine in patients treated with HAART for over two years. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 346. Jin X and others. Discontinuation of HAART after a course of therapeutic vaccination with ALVAC1452 and rgp160 with delayed viral rebound kinetics. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. LB 12. HIV RESISTANCE AND RESISTANCE TESTING HIV RESISTANCE IN PRIMARY HIV INFECTION Investigators from Montreal presented data on prevalence of dual and tripleclass resistance to protease (PR), nonreverse transcriptase (NNRT) and nucleoside reverse transcriptase (NRT) inhibitors in 87 patients with primary/early HIV1 infection studied from 1997 to 1999. The prevalence of dual and tripleclass drug resistance is 12% and 2%, repectively. This study confirms what others have reported at previous conferences and also in two recent articles in the Journal of the American Medical Association, cited previously in the HIV News section of this issue of Numedx. This emerging problem of antiretroviral drug resistance also has some bearing on the study by Cohen discussed below. Routy, JP et al. Transmission of dual and tripleclass drugresistant viral variants in primary/early HIV1 infection (PHI) in Montreal. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 567. RESISTANCE TESTING AND DRUG SELECTION Choosing antiretroviral drugs based on the results of phenotypic HIV resistance testing allows for better viral suppression compared with treatment decisions based on the current standard of care. Dr. Calvin Cohen of the Community Research Initiative of New England studied 111 patients whose drug regimens were determined by the Virco Antivirogram assay and 107 whose subsequent treatments were determined without resistance testing after failing their first PIcontaining HAART regimen. The 16week study showed that virologic outcome is improved, with 62% and 33% of patients having viral loads <400 copies in the antivirogram group vs standard of care group, respectively. This study adds to the emerging data base that shows the value of resistance testing in HIV care. Certainly genotype and phenotype testing are useful in drug selection for patients who have failed a previous regimen. Presumably, better drug selection not only improves outcome but has the potential to help manage drug costs. Cohen, C. Phenotypic resistance testing significantly improves response to therapy (Tx): A randomized trial (VIRA 3001). Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 237. HAART AND SECONDARY PROPHYLAXIS FOR PNEUMOCYSTIS CARINII PNEUMONIA (PCP) It has been shown previously that primary prophylaxis for PCP can be stopped in patients on HAART without increasing the risk of PCP if the CD4 count increases to >200 cells. The authors of a new study conclude that the risk for recurrent PCP after a CD4 count increase to at least 200 cells per microliter resulting from HAART is the same as that for primary PCP. They also conclude that the current USPHS/IDSA Guidelines for discontinuing PCP prophylaxis after HAART should be expanded, to include secondary prophylaxis as well. However, it is still important to monitor CD4 counts in our patients and resume PCP prophylaxis if the CD4 count decreases to <200 for any reason. Ledergerber B and others. It is safe to discontinue secondary prophylaxis for PCP in HIVinfected patients treated with HAART: Results from eight prospective European cohorts. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract LB 5. SHOULD TWO PEOPLE WITH HIV PRACTICE SAFER SEX/BARRIER PRECAUTIONS? According to a Canadian investigator, the answer is still yes. Angel et al described what they called the first report of HIV1 superinfection, followed by more rapid progression of HIV disease. Their conclusions were based on the results of genotypic analysis of 2 male patients who were in a sexual relationship. The results showed significant homology or similarity between genetic sequences of protease and reverse transcriptase genes in both patients, compared with control HIVpositive patients, whose genetic sequencing were more easily distinguishable. The fact that HIV1 infection does not necessarily result in resistance to subsequent infection has significant public health and populationbased implications and emphasizes the importance of safer sexual practices between HIVinfected persons. Angel JB, et al. Documentation of HIV1 superinfection and acceleration of disease progression. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract LB 2. Drug interactions between amprenavir and ritonavir can be beneficial. A study of 18 healthy seronegative adults was presented showing that ritonavir increases the area under the curve (AUC) of amprenavir and allows for lower dosages of amprenavir, resultssimilar to earlier studies showing interactions between lowdose ritonavir and the protease inhibitors indinavir, nelfinavir, and saquinavir. This pharmacokinetic study concluded that amprenavir 450 mg + ritonavir 100 mg, both given q 12 hours, showed an increase in amprenavir concentration to more than 10 times the IC50 (concentration to inhibit 50% of virus) of wildtype virus. This dosing did not affect serum glucose and was assiciated with fewer side effects than 300 mg q 12 hours of ritonavir. Sadler BM, et al. Pharmacokinetic (PK) druginteraction between Amprenavir (APV) and Ritonavir (RTV) in HIVseronegative subjects after multiple, oral dosing. Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections, January 30February 2, 2000, San Francisco, Calif. Abstract 77. Presentations at this conference continued to focus on the convergence of treatment strategies that have the potential to make HIV a chronic, manageable illlness for more people. These converging strategies include the role of immune function and its preservation and restoration in addition to antiretrovirals, resistance testing, and the use of new technologies to guide therapy and monitor the effects of treatment and treatment adherence. |
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