1/10. Strategies for long-term success in the treatment of HIV infection.Highly active antiretroviral therapy has revolutionized the treatment of human immunodeficiency virus (HIV) infection, which can now be viewed as a chronic and manageable disease. However, HIV infection differs from other chronic diseases in that early treatment decisions can irrevocably alter the patient's response to future therapy. Despite the large number of approved antiretroviral agents, the number of sequential treatment regimens that will be effective for an individual patient is sharply limited by cross-resistance within the 3 drug classes. Because of the complexity of antiretroviral therapy, clinicians prescribing it require considerable expertise. Treatment should be deferred until the patient has been educated about the importance of strict adherence and has demonstrated willingness and motivation to begin therapy. Drug regimens should be chosen that the patient can tolerate and adhere to, and the consequences of resistance should be considered before therapy is begun. When treatment fails, the timing and choice of subsequent therapy can be critical in determining the magnitude and durability of response. Resistance testing can help guide the clinician in the choice of therapy. In patients who have been treated with numerous antiretroviral agents, it may be impossible to achieve significant viral suppression. Therapy may still be beneficial for such patients, but it should be tolerable and should not increase resistance to drugs that may become available in the near future. drug resistance and treatment failure are not random events, but are the result of factors over which clinicians and their patients have some control. The treatment of drug-resistant patients is challenging; the best way to deal with resistance is to prevent it.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
2/10. carbamazepine--indinavir interaction causes antiretroviral therapy failure.OBJECTIVE: To report a case of antiretroviral therapy failure caused by an interaction between carbamazepine and indinavir. CASE SUMMARY: A 48-year-old HIV-positive white man was treated with antiretroviral triple therapy, consisting of indinavir, zidovudine, and lamivudine. His HIV-rna (viral load) became undetectable (<400 copies/mL) less than two months after this therapy was started; this was confirmed one month later. Shortly after the start of antiretroviral therapy, the patient developed herpes zoster, which was treated with famciclovir. tramadol was initially prescribed for postherpetic neuralgia; however, this was substituted with carbamazepine due to insufficient analgesic effect. indinavir plasma concentrations decreased substantially during carbamazepine therapy. carbamazepine was stopped after 2.5 months and, two weeks later, the HIV-rna was detectable (6 x 103 copies/mL). Resistance for lamivudine was observed in that blood sample; resistance for zidovudine might have been present, and resistance to indinavir was not detected. A few months later, a further increase of the HIV-rna occurred (300 x 103 copies/mL), after which the therapy was switched to a new antiretroviral regimen containing nevirapine, didanosine, and stavudine. DISCUSSION: physicians may prescribe carbamazepine for HIV-infected patients to treat seizures or postherpetic neuralgia, which are complications of opportunistic infections such as herpes zoster or toxoplasmosis. carbamazepine is a potent enzyme inducer, predominantly of the CYP3A enzyme system, while HIV-protease inhibitors such as indinavir are substrates for and inhibitors of CYP3A. Therefore, an interaction between these drugs could be expected. A low dose of carbamazepine (200 mg/d) and the usual dose of indinavir (800 mg q8h) in our patient resulted in carbamazepine concentrations within the therapeutic range for epilepsy treatment; indinavir concentrations dropped substantially. The virologic, resistance, and plasma drug concentration data, as well as the chronology of events, are highly indicative of antiretroviral treatment failure due to the interaction between carbamazepine and indinavir. CONCLUSIONS: Concomitant use of carbamazepine and indinavir may cause failure of antiretroviral therapy due to insufficient indinavir plasma concentrations. Drugs other than carbamazepine should be considered to prevent this interaction. amitriptyline or gabapentin are alternatives for postherpetic neuralgia; valproic acid or lamotrigine are alternatives for seizures. When alternate drug therapy is not possible, dosage adjustments, therapeutic drug monitoring, and careful clinical observation may help reduce adverse clinical consequences.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
3/10. pol gene sequence variation in Swedish hiv-2 patients failing antiretroviral therapy.There is limited knowledge about how to treat and interpret results from genotypic resistance assays in hiv-2 infection. Here, genetic variation in hiv-2 pol gene was studied in 20 of 23 known hiv-2 cases in sweden. Five patients with signs of virological treatment failure were longitudinally studied. Clinical, virological and immunological data were collected and the protease (PR) and first half of the reverse transcriptase (RT) was amplified and directly sequenced from plasma samples. Moderate to extensive genetic evolution was observed in four of the five patients who failed treatment. Some mutations occurred at positions known to confer resistance in hiv-1, but many occurred at other positions in PR and RT. All patients had been treated with zidovudine alone or in combination with other antiretroviral drugs, but none displayed a mutation at position 215, which is the primary zidovudine resistance site in hiv-1. Instead, a E219D mutation evolved in virus from two patients and a Q151M mutation evolved in two other patients. A M184V mutation indicative of lamivudine resistance was detected in three patients. The virus of one patient who had been treated with ritonavir, nelfinavir, and lopinavir successively acquired nine unusual mutations in the protease gene, most of which are not considered primary or secondary resistance mutations in hiv-1. Our data indicate that the evolutionary pathways that lead to antiretroviral resistance in hiv-2 and hiv-1 exhibit both similarities and differences. Genotypic hiv-2 resistance assays cannot be interpreted using algorithms developed for hiv-1, instead new algorithms specific for hiv-2 have to be developed.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
4/10. A 6-base pair insertion in the protease gene of HIV type 1 detected in a protease inhibitor-naive patient is not associated with indinavir treatment failure.Insertions in the protease gene of hiv-1 were rarely found and are not associated with reduced effectiveness of protease inhibitors although they are thought to be selected by protease inhibitor therapy. This is the first report of a 6-basepair insertion in the protease gene prior to protease inhibitor therapy.- - - - - - - - - - ranking = 4keywords = treatment failure (Clic here for more details about this article) |
5/10. Failure of hiv-2 viral load assay in a severely immunodeficient patient: clinical and therapeutic management issues.We report the case of an hiv-2-infected patient with severe immunosupression despite undetectable plasma hiv-2 rna. This immunovirological discordance was due to failure of the viral load assay and infection by an unknown hiv-2 subtype. Treatment was probably suboptimal, leading to the selection of several resistance mutations and treatment failure.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
6/10. Immune reconstitution syndrome in a child with TB and HIV.Immune reconstitution syndrome (IRS) is the transient worsening or appearance of new signs, symptoms or radiological manifestation of an opportunistic infection occurring after the initiation of Highly active antiretroviral therapy (HAART) and is not due to treatment failure or new infection. We describe a case of a HIV infected child with tubercular (mediastinal) lymphadenitis with worsening of clinical and radiological features on starting HAART.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
7/10. hiv-1 infection despite immediate combination antiviral therapy after infusion of contaminated white cells.We present a sixth human case in which primary human immunodeficiency virus (hiv-1) infection occurred, despite antiretroviral prophylaxis, after accidental inoculation of infected blood. In the prior five instances, variables such as large virus dose, late administration of antivirals, viral resistance to zidovudine, and pre-existent immunosuppression, may have played a role in the treatment failure. In this case, high-dosage oral zidovudine was given within minutes of the accident and replaced 2 1/2 days later with interferon alpha and dideoxyinosine (ddl). Despite aggressive treatment, hiv-1 infection was demonstrated in blood, spleen, and brain tissue at autopsy 16 days later. Of the tissues studied, detection of hiv-1 was most prominent in the spleen. Double-label immunocytochemistry confirmed the morphologic impression that while some of the infected spleen cells were CD3-positive T cells, the majority were macrophages. Thus, current single or dual (zidovudine, ddl-interferon) therapies for accidental hiv-1 inoculation may not be effective in preventing early infection. Further trials in animals appear warranted to evaluate protection by other strategies, such as passive immunity or combinations of agents that penetrate the brain and attack hiv-1 viral replication at differing sites.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
8/10. Disseminated strongyloides stercoralis in human immunodeficiency virus-infected patients. treatment failure and a review of the literature.We describe a North American human immunodeficiency virus (HIV)-positive patient with strongyloides stercoralis infection of the gastrointestinal tract, who required repeated "standard" courses of thiabendazole. Pulmonary infection with numerous roundworms developed, as suspected by bronchoalveolar lavage, and while he was receiving therapy, dissemination occurred. On autopsy, S stercoralis was recovered in the gastrointestinal tract, liver, lung, and heart. After a literature review, we conclude that HIV-positive patients have a higher risk of dissemination and "standard" treatment failure. This may occur without elevation of IgE or eosinophilia. Those patients may require prolonged courses of thiabendazole or alternatively ivermectin therapy.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
9/10. The pathophysiology of pure red cell aplasia: implications for therapy.To determine the utility of marrow culture in defining the natural history and therapeutic response of pure red cell aplasia we have studied 37 patients. patients were evaluated at the University of washington before specific therapies (n = 21) or at the time of treatment failure in = 16). Evaluation included a medical and drug exposure history, a physical examination, a chest x-ray or computed tomography to rule out thymoma, lymphocyte immunophenotype studies, anti-nuclear antibody and rheumatoid factor determinations, marrow cytogenetics, and marrow progenitor cell cultures. Retrospective Southern analyses to detect human parvovirus B19 was performed in the 27 patients for whom sera was stored. Clinical follow-up was obtained to document therapeutic responses. Normal burst forming unit-erythroid (BFU-E) growth (>30 bursts/10(5) marrow mononuclear cells [MMNC]) in culture proved an outstanding predictor of clinical response, as 27 of 29 individuals with normal frequencies of erythroid bursts in culture responded to immunomodulating therapies (sensitivity 96%, specificity 78%, predictive value 93%, P = .0001 with two-tailed chi square analysis). overall, 28 patients responded to either immunomodulating therapies or drug withdrawal. Twenty-four patients obtained a normal hematocrit (complete response [CR] and 4 additional patients became transfusion independent (partial response). Although responding patients often required several therapies, 20 of 24 (83%) patients who obtained a CR have sustained a normal hematocrit without maintenance therapy at the time of last follow-up (median 5 years). In contrast, of 8 patients with poor in vitro BFU-E growth (<6 bursts/10(5) MMNC), 7 failed to respond to any therapy and all died (median survival time 17 months). Our data suggest that in individuals, from whom BFU-E mature appropriately in culture, immunosuppressive drugs should be used sequentially until a CR is obtained and a durable remission is the expected outcome.- - - - - - - - - - ranking = 1keywords = treatment failure (Clic here for more details about this article) |
10/10. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients.BACKGROUND: Despite the use of directly observed therapy (DOT) by tuberculosis control programs, patient treatment failure, relapse, and acquired drug resistance remain problematic in a small number. We investigated serum drug levels in non-HIV-infected tuberculosis patients who were receiving DOT by the health department and did not respond to treatment as expected. methods: The indications for checking levels were as follows: (1) slow clinical response or failure to convert the sputum culture within 12 weeks; (2) treatment failure, early disease relapse < 13 months since being declared cured; (3) relapse, late disease reactivation > or = 13 months since being declared cured; and (4) acquired drug resistance while receiving DOT. Baseline characteristics of control subjects who responded to therapy as expected were compared. Venous blood for analysis was obtained at 2 h after directly observed ingestion and measured by high-performance liquid chromatography. RESULTS: Twenty-four patients receiving daily or twice-weekly standard therapy with isoniazid (INH, 300 or 900 mg) and rifampin (RMP, 600 mg) were identified; 22 had drug levels evaluated at 2 h. For INH, 15 of 22 patients (68%) had levels less than the reported target range. For RMP, 14 of 22 patients (64%) had low levels. Among the 14 patients receiving INH, 900 mg, and RMP, 600 mg, 4 (29%) had very low levels of both. Use of a combination INH/RMP tablet was associated with lower INH levels (p=0.04); however, RMP levels were higher (p<0.02). Alcohol use was associated with significantly higher RMP (p<0.01) serum concentrations. CONCLUSIONS: Important questions remain concerning the utility and timing of serum drug measurements. However, if a patient is not responding to therapy as expected and one is assured that the mycobacterium tuberculosis organism is susceptible to the drugs given and that the patient is taking the medication as prescribed, drug level monitoring should be considered.- - - - - - - - - - ranking = 2keywords = treatment failure (Clic here for more details about this article) |
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