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Treatment Interruption Studies at Bangkok IAC
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Reported by Jules Levin
We have come a long way since the IAC in South Africa. Back then the risks of treatment interruptions were not given much scrutiny or consideration. Following the conference mainstream newspaper headlines screamed the potential benefits and not the risks for interruptions. Patients paid attention to these headlines and very often felt interruptions were beneficial and not risky. As well, many doctors felt the same. Since this time much more study and due consideration has identified many of the risks of treatment interruption. Since this time much more study and due consideration has identified many of the risks of treatment interruption. The risks of interruption have been communicated to many, but there remains I think a substantial portion of patients and others who don't understand the risks. Just this year at the 11th CROI (Retrovirus Conference) researchers made a big impact with the finding that efavirenz, not unlike nevirapine & 3TC, can remain in the blood for days after stopping HAART, and this might lead to NNRTI resistance. In recent years at Resistance Workshops, a series of studies have found that when stopping therapy resistance can develop to drugs that have a long half like, such as 3TC and NNRTIs. I have selected a compilation of studies on interruption presented at Bangkok, which I think were relevant & provide thoughtful and helpful information.
So, caution is advised when considering treatment interruption. There is no question that taking therapy day in and day out for years can be difficult. In some cases patients may refuse to continue therapy and emphatically want to interrupt therapy. In those cases it might be worth considering a well-planned interruption rather than risking non-adherence. When considering an interruption one should assess the potential benefits and consider the risks. Discuss this with a knowledgable physician and plan properly. If taking drugs with long half lifes it's important to stop therapy in a way that will not encourage drug resistance. It is also important to monitor viral load and CD4 counts after stopping therapy.This paragraph is by no means meant to encourage interruptions, but to encourage due consideration of taking an interruption.
Here are several studies presented at the Bangkok Intl AIDS Conference regarding treatment interruptions. These studies provide differing results & different perspectives. One thing we do not have is an understanding of the long-term consequences of treatment interruptions and repeated interruptions. Do they damage the immune system? This is a concern that has been raised but to which we don't have an answer.
For patients whose Cd4 count was never below 500 but started HAART because the Treatment Guidelines previously recommended starting HAART when CD4s are 500, studies have found that in general CD4 counts do not decline too quickly and interruptions appear safe. But monitor the CD4 count to check for declines. For patients with low CD4 nadir, that is patients who have had declines in CD4 count to low levels, there is concern about an interruption. Studies and clinical experience have found that after interrupting HAART in general CD4 count can have a quick decline. One of the studies below addresses the question of resistance.
There are two important points to make regarding drug resistance. When a patient has HIV drug resistance, it gets archived. This means it may not be seen upon doing a commercial resistance test but it appears as if it will always present, never truly disappears. When interrupting therapy, even if drug resistance disappears (not found in genotypic tests), upon restarting therapy it is expected to return. This may affect the regimen you have restarted. Second, certain drugs develop resistance to them easily. These include 3TC, nevirapine, efavirenz and FTC. Resistance to these drugs develops easily & quickly because you only need one resistance mutation to virologically fail the drug. In contrast, protease inhibitors require several genotypic drug mutations before viral failure can occur so in general it is more difficult to develop drug resistance to protease inhibitors. These 4 drugs I mentioned just above have long half lifes, they last a long time in the blood. So after stopping therapy these drugs remain in the blood at decreasing levels for days, but the other drugs in the regimen disappear more quickly from the blood. Therefore, there is a risk of developing resistance to these drugs after stopping a regimen. Repeated interruptions or missed doses can encourage this to occur. If discontinuing one of these drugs you can consider switching drugs in your regimen—perhaps to a boosted protease inhibitor and drugs with a short half life—prior to interruption. This might prevent drug resistance to these drugs from developing.
Once you get HIV drug resistance it is archived, it appears as though it never truly goes away. One last point regarding resistance. A recent development has been observed in the past year. Several studies have found that even when commercial resistance tests do not find HIV drug resistance, sensitive resistance tests can find drug resistance. So, you may not find drug resistance but it may still be present. When evaluating whether or not resistance is present, it is important to use your judgement in assessing HIV treatment history.
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This stud raises an interesting concern. If a patient interrupts therapy and their undetectable viral load becomes detectable there is an increased risk for transmission of HIV and transmission of drug resistance, so risky behavior and the presence of STDs should be considered and evaluated.
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HIV transmission risk among patients enrolled in a large clinical trial evaluating treatment interruption
W Burman1, J Neuhaus2, C Rietmeijer1, J Douglas1, C McCartin3
1Denver Public Health, Denver, CO, United States; 2Univeristy of Minnesota, Minneapolis, MN, United States; 3Denver CPCRA, Denver, CO, United States
Background: There is growing emphasis on providing prevention services to persons in HIV care, but there is a need for more information on the frequency of and the factors associated with transmission risk among persons in care. We evaluated HIV transmission risk among a subset of patients enrolling into the SMART study (an interruption study).
Methods: Sexual and needle-sharing behavior during the 2 months prior to enrollment was determined from a confidential questionnaire; patients were also tested for gonorrhea and chlamydia using urine DNA amplification tests. "High-risk" was defined by self-reported behavior (anal or vaginal sex without a condom or needle-sharing) or a positive urine test for gonorrhea or chlamydia.
Results: Patients were enrolled from 9 geographically dispersed sites and had demographic characteristics similar to patients with HIV infection in the U.S. (23% women, 38% Black, 14% Hispanic, 53% homosexual men). 86 of 472 patients (18.2%) met the criteria for high risk for HIV transmission, most because of self-reported behavior; only 5 (1%) had a positive urine test (all for chlamydia). HIV transmission risk did not differ significantly by age, race/ethnicity, likely mode of HIV acquisition, sexual orientation, history of AIDS, current or nadir CD4 cell count, current use of antiretroviral therapy, or self-reported adherence to antiretroviral therapy. The rate of high-risk behavior was somewhat higher among women than men (26.2% vs. 15.9%, p=0.009 in multivariate analysis). Among patients with high-risk behavior, 51% had complete viral suppression at enrollment, but 25% had at least one major resistance mutation in plasma virus.
Conclusions: High risk behavior is relatively common among persons enrolling in the SMART study, and the rates vary little by demographic and clinical criteria.
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CD4 Counts Can Be Used As Cut-off for Structured Treatment Interruption
(Reuters, July 13, Bangkok IAC) In a small pilot trial, more than half of the HIV-infected patients were able to discontinue antiretroviral therapy for up to 2 years, using a decline in CD4 counts to less than 350 cells per microliter as a threshold to reinitiate treatment, researchers reported Tuesday at the XV International AIDS Conference.
"Seventy percent are off therapy, and doing well, without any real problems for almost 2 years with very little indication that their CD4 cells are dropping," lead investigator Dr. David A. Katzenstein of Stanford University in California told Reuters Health.
"Many people have done structured treatment interruption studies that have used rebound in viral load as the indication to resume treatment." In this study "we have used a CD4 cell threshold, rather than reacting to the virus load," he pointed out.
Dr. Katzenstein and members of the ACTG A5102 group randomized 47 patients to receive IL-2 for 18 weeks in addition to their regular antiretroviral therapy, or to continue on their antiretroviral regimen only. The purpose of IL-2 therapy was to boost CD4 counts as much as possible.
"The only condition for enrollment was that they were on their first potent HAART regimen, that they had more than 500 CD4 cells, and that they had undetectable HIV RNA," he said.
The patients' median baseline CD4 counts were 810 cells per µL and 96% had HIV RNA levels below 50 copies per mL. Although the IL-2 group had higher CD4 counts, "IL-2 didn't make that much of a difference," Dr. Katzenstein said. Specifically, the median CD4 counts achieved were 1331 cells/microliter in the IL-2 group and 757 cells/microliter in the other group.
Both patient groups then discontinued all treatment. Patients were restarted on treatment if their CD4 counts fell below 350 cells per microliter.
Overall, there were five patients in the first year and seven in the second year whose CD4 cells actually did drop below 350 copies per microliter, Dr. Katzenstein noted. However, "they just went back on treatment and they're doing fine."
He speculated that patients with lower nadir CD4 counts and higher baseline viral loads may not be good candidates for this treatment-sparing strategy.
In the current study, virus loads rebounded "quite promptly and some of them alarmingly in terms of very, very, high virus loads," Dr. Katzenstein pointed out. However, "We saw only two cases of acute retroviral syndrome - people who had any symptoms from that acute viremia."
He added, "I think people always feel more comfortable knowing that their virus load is suppressed, but in fact viremia doesn't appear to be that bad for you. There were lots of concerns about this, but it turns out the patients did fine."
With increased global access to treatment, there are going to be millions of people who are doing very well on antiretroviral therapy for many years, "so I think we need to be looking forward to strategies of how can we can safely interrupt it to spare (patients) some the toxicities of treatment," Dr. Katzenstein commented.
"We can continue to gather this kind of data in small, carefully controlled cohorts in the US, and then ask how that can impact and improve access in the developing world," he concluded. "This may be a very, very good cost-saving and toxicity-saving device if we can learn how to use it properly."
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DIFFERENT EXPERIENCE WITH TREATMENT INTERRUPTIONS -- Fast CD4 Loss
Dynamics of immunologic decline and virological rebound during treatment interruption in chronic HIV disease: The CHORUS cohort
R Mera1, B Most2, R B Balu2, J Fusco2
1GlaxoSmithKline, Collegeville, PA , United States; 2CHORUS, GlaxoSmithKline, Research Triangle Park, NC, United States
Background: Although HAART substantially suppresses virus replication, treatment interruptions (TI) occur for numerous reasons. For therapeutic vaccine trials, a period of structured treatment interruption may be necessary. It is important to gauge the implications of TIs in an observational setting, prior to the conduction of trials that require patients to stay off therapy.
Methods: Using data from CHORUS, patients with TIs were matched with patients who did not interrupt (controls) on the basis of time era filters and propensity scores that took into account baseline sociodemographic and clinical variables, resulting in 337 cases and 1067 controls. Marginal structural models using inverse probability of treatment weighting methodology were utilized to compare virological and immunological profiles of cases and controls.
Results: Patients with controlled viremia had an average peak VL of 14,500 cpm at 9 weeks post-interruption; patients with uncontrolled viremia had a peak of 165,000 cpm at 4 weeks. Patients with a CD4 nadir 50-200 and 350-500 cells had peak VLs of 50,000 cpm and 15,000 cpm respectively.
Patients with uncontrolled viremia had a median of 73 CD4 cells at baseline and had lost 20% in the first month and 45% by the sixth month after interruption. By contrast, the well-controlled patients started with a median of 679 cells and lost 10% in the first month, and ~25% by the sixth month. Patients with CD4 nadir between 50-200 and 350-500 cells lost 32% and 19% of the circulating CD4 cells at six months post-TI.
Conclusions: Most of the patients in this study failed to control viral replication during the interruption. There was a significant depletion of CD4 cells among patients with low CD4 nadir who had a long TI. The use of structured treatment interruptions in combination with therapeutic vaccines should be undertaken after careful evaluation of results of this and other studies aimed at assessing disease progression in the absence of therapy.
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Predictive factors of failure antiretroviral treatment interruption (TI) in chronic stable HIV-infected patients
R Torres, M Cervero, J Jusdado, M Del Alamo, J Solís
H. Severo Ochoa, Madrid, Spain
Background: Treatment interruptions is an strategy in the management of HIV-infected patients. A predictive model of factors associated with failure TI, could be interesting to support this practice.
Methods: We conducted in Spain a follow-up study on 44 patients.We made a multivariate regression analysis to examine predictive factors associated with failure TI. Reasons to TI were patient-decision, toxicity or physician-decision (in asymptomatic patient who started HAART at CD4 level > 500 cell/ml. We considered failure TI when CD4 level decline to < 350 cell/ml, or if patients developed any event related- HIV.
Results: 44 patients with TI were examined, with a median follow-up 13 months. Reasons were : lipodistrophy 2; severe hepatic toxicity 6; cardiovascular complications 2; patient decision 11, and physician decision in 23 cases. 12 (27.3%) restarted therapy: 6 due to low CD4 < 350, and 6 due to clinic events (oral candidiasis 1, thrombocytopenia 1, acute retroviral syndrome 2, P.carinii pneumonia 1 and pulmonary tuberculosis 1). All patients who restarted antiretroviral therapy regained similar CD4 counts and HIV-VL than prior to TI. In univariable analysis, nadir CD4 <350 cell/ml (p=0.003), CD4 at the beginning of treatment < 350 cell/ml (p=0.073), VL at TI < 50 cps/ml (p=0.021) and time of undetectable VL lower 6 months prior TI (p=0.011) were associated with failure TI. However, only we can make the predictive model of failure TI with nadir CD4 and time of VL undetectability: OR nadir CD4 7,45 (IC 95% 1,48-37,5) and OR Time VL undetectable 5,9 (IC 95% 0,97-35,9). AUC 0.82 (IC 95% 0,68-0,95).
Conclusions: Nadir CD4 and time of HIV-VL undetectable prior to TI are two predictive factors of failure TI (probability of failure TI is 0.73). Treatment interruption is safe in absence of these factors and contributes to remove related toxicity, improve quality of life and decrease costs.
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Genetic characterization of rebounding HIV-1 after interruption of HAART in chronic patients with suppressed viremia
S Rusconi1, E Bulgheroni1, P Citterio1, M Lo Cicero1, F Soster1, O Viganò1, F Croce1, L Sutton2, R T D'Aquila2, M Galli1, M P De Pasquale2
1University of Milan, Milan, Italy; 2Vanderbilt University, Nashville, TN, United States
Background:
Although is not surprising that viral rebound occurs in HIV-infected patients (pts) after discontinuation of HAART, the source of plasma rebounding virus remains uncertain. We examined the rebounding virus in plasma after interruption of HAART in 4 chronically infected individuals in whom successful suppression of viremia had been achieved for considerable periods of time.
Methods:
HIV RNA was extracted from blood plasma, culture supernatant and semen plasma. PBMC proviral DNA was extracted. pol region was amplified and sequenced. Phylogenetic analysis of sequences was performed by the neighbor-joining algorithm and by the Kimura method. Genetic distances were estimated by DNADIST.
Results:
3 chronically infected pts with blood viremia <50 cp/ml for > 2 years interrupted their treatment. A fourth patient had viremia < 50 cp/ml by bDNA and 2156 cp/ml by PCR when dropped the therapy. In 3 out of 4 pts the rebounding virus harbored mutations associated with resistance to previous regimens (41L, 70R, 184V, 219Q in RT). The sequences from each individual patient clustered together irrespectively of their source of origin w/o evidence of contamination. In 2 pts the baseline plasma sequences showed differences from the corresponding proviral DNA and the replication-competent virus isolated from CD4+ cells at matching time, suggesting that ongoing, low level replicative virus may traffic into blood from sanctuaries tissues. In 3/4 pts viral quasispecies emerging after treatment interruption showed a tighter homology: the genetic distances between pol sequences at early and later timepoints were < 5.3%.
Conclusions:
We evaluated the genetic homology of rebounding virus in 4 chronically infected pts undergoing treatment interruption after a prolonged time of suppressed viremia.
The data from 2 pts suggest that the virus circulating in blood when therapy was suspended may be of a different lineage than the PBMC proviral DNA. In some cases the rebounding virus at following timepoints was more genetically related and harbored resistance mutations.
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Fatal interruption of a 3TC-containing regimen in a HIV-infected patient
P Clevenbergh1, P Sellier1, M Mazeron2, D Cazals-Hatem3, J Evans4, J Cervoni5, E Badsi5, M Bendenoun5, M Diemer5, V Vincent5, C Caulin5, J Bergmann5
1Internal Medicine Dpt, Lariboisière Hospital , Paris, France; 2Virology, Lariboisière Hospital, Paris, France; 3Anatomopathology Dpt, Beaujon Hospital, Clichy, France; 4Internal Medicine Dpt, Paul Brousse Hospital, Villejuif, France; 5Internal Medicine Dpt, Lariboisière Hospital, Paris, France
It is suggested that if taking 3TC and HBV is present, if you want to take tenofovir or adefovir maintain 3TC therapy after the addition of the new drug.
Introduction:
Ten % of HIV-infected individuals are hepatitis B virus (HBV) surface antigen-positive (HBs Ag). First line anti-HIV therapy usually contains lamivudine (3TC), a reverse transcriptase inhibitor with antiviral activity against both HIV and HBV. Interrupting 3TC can lead to severe hepatitis and death.
Case report:
A 58-year-old man was diagnosed HIV-HBV co-infected in 1992. HBV serology revealed HBs Ag +, HBs antibody (Ab) -, HBc Ab +, Hbe Ab + and plasma HBV DNA present. Stavudine and 3TC were begun in December 1996 with complete suppression of HIV and HBV replication. In March 1999, nevirapine was added to this regimen. In Augustus 2000, HIV genotypic resistance testing revealed mutations at positions M41L, K103N, Y181Y/C, M184V, T215Y. HBV DNA was still undetectable. HIV therapy was changed to stavudine, didanosine, indinavir. In september 2000, the patient was admitted for acute hepatic failure. Serology showed HBs Ag +, HBs Ab -, HBc IgM +, Hbe Ag +, Hbe Ab -, HBV DNA: 5.7 Meq/mL. He died the next day. A post-mortem hepatic biopsy revealed active HBV replication.
Discussion:
HIV and HBV use a reverse-transcriptase that is inhibited by some nucleoside or nucleotide analogues. They tend to acquire resistance mutation, a process accelerated in the context of monotherapy. Resistance mutations decrease their replicative capacity and pathogenicity. They exhibit a virologic rebound after stopping therapy or when the virus has become resistant to it, associated with manifestations ranging from clinically silent to acute infection. They establish lifelong reservoirs in the liver (HBV) and/or lymphatic system (HBV, HIV) and their eradication is elusive. The major difference is their viral dynamics, where HIV acquires resistance faster than HBV and drives treatment change. Concomitant treatment of both viruses is complicated and can be dangerous. Once 3TC had been started, when and how to stop it remain unresolved questions.
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