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Sexually Transmitted Infections Aug 2003To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors... (Review)
Review
OBJECTIVE
To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors associated with this complication.
METHODS
Systematic review of cases reported in the medical literature.
RESULTS
217 published cases were identified, 90 of which fulfilled the study definition and had sufficient individual data on potential risk factors to be included. The 90 patients had a mean age of 40.1 years (range 16-69) and 53% were female. All 90 patients were taking nucleoside reverse transcriptase inhibitors (NRTI) at the time of the episode. Among the 83 patients with details of their antiretroviral therapy (ART) regimen 51 patients were taking stavudine, 29 zidovudine, 27 didanosine, and 25 lamivudine. Around 50% of the patients had abdominal pain, nausea, or vomiting. Hepatic steatosis was consistently reported (53/90) and in 36 (68%) there was histological evidence. The case fatality rate was 48%. Six cases were rechallenged with NRTI and three developed a further LA episode. Using data on the numbers of HIV infected individuals receiving care in the United States, we estimate that the risk of LA could be 2.5 times higher for women than men.
CONCLUSIONS
NRTI use and female sex appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include duration of NRTI therapy, specific drug use, and genetic predisposition. A case-control study is needed to better define risk factors for severe LA.
Topics: Acidosis, Lactic; Adolescent; Adult; Aged; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Reverse Transcriptase Inhibitors; Risk Factors
PubMed: 12902594
DOI: 10.1136/sti.79.4.340 -
Clinical Infectious Diseases : An... May 2003We analyzed the available evidence about the efficacy and tolerability of once-a-day highly active antiretroviral therapy (HAART), searching databases, conference...
We analyzed the available evidence about the efficacy and tolerability of once-a-day highly active antiretroviral therapy (HAART), searching databases, conference proceedings, and journals. Two reviewers independently selected 6 uncontrolled and 2 randomized clinical trials of at least 24 weeks duration and with 80% participant follow-up. Regimens included didanosine (ddI), emtricitabine (FTC), and efavirenz (EFV) (2 studies, 326 patients); ddI, lamivudine (3TC), and EFV (3 studies, 147 patients); ddI, 3TC, EFV, and adefovir dipivoxil (1 study, 11 patients); ddI, nevirapine, and EFV (1 study, 15 patients); and ddI, 3TC, indinavir, and ritonavir (1 study, 10 patients). Virological efficacy ranged between 70% and 91%. Preliminary randomized clinical trials showed that once-a-day regimens (ddI, 3TC, and EFV or ddI, FTC, and EFV) had a virological efficacy at least similar to that of conventional HAART. The overall CD4 cell increase was at least 114 lymphocytes/microL. Tolerability was good, with a low discontinuation rate.
Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; Drug Tolerance; Female; HIV; HIV Infections; Humans; Lymphocytes; Male; RNA, Viral; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load
PubMed: 12715315
DOI: 10.1086/374602 -
International Journal of Infectious... 2001Effective antiretroviral therapy remains beyond the reach of most human immunodeficiency virus (HIV)-infected persons living in the third world because of its tremendous... (Review)
Review
Effective antiretroviral therapy remains beyond the reach of most human immunodeficiency virus (HIV)-infected persons living in the third world because of its tremendous cost. The cancer drug, hydroxyurea, inhibits HIV-1 replication in vitro and, when combined with didanosine (ddI), results in significant antiretroviral synergy. In vivo, hydroxyurea specifically targets quiescent lymphocytes and macrophages, important cellular reservoirs for HIV-1, and the combination of ddI plus hydroxyurea effectively reduces plasma HIV-1 RNA levels. Combination ddI-hydroxyurea costs about one-eighth as much as currently recommended triple drug combinations, and several countries in Africa are exploring the feasibility of widescale use of ddI-hydroxyurea for their HIV-infected populations. Intrigued by its potential relevance for Africa, the authors reviewed the literature on the in vitro and clinical efficacy of ddI plus hydroxyurea against HIV. The combination of ddI plus hydroxyurea is an effective and potentially more affordable regimen for HIV-infected persons living in poorer countries.
Topics: Africa; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hydroxyurea; MEDLINE; Treatment Outcome; Viral Load; Zidovudine
PubMed: 11285159
DOI: 10.1016/s1201-9712(01)90048-7 -
The Cochrane Database of Systematic... 2000Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). (Review)
Review
BACKGROUND
Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC).
OBJECTIVES
To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival.
SEARCH STRATEGY
Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts.
SELECTION CRITERIA
Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events.
DATA COLLECTION AND ANALYSIS
Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials.
MAIN RESULTS
Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009).
REVIEWER'S CONCLUSIONS
The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Zalcitabine; Zidovudine
PubMed: 10908523
DOI: 10.1002/14651858.CD002038 -
The Cochrane Database of Systematic... 2000Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). (Review)
Review
BACKGROUND
Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC).
OBJECTIVES
To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival.
SEARCH STRATEGY
Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts.
SELECTION CRITERIA
Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events.
DATA COLLECTION AND ANALYSIS
Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials.
MAIN RESULTS
Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009).
REVIEWER'S CONCLUSIONS
The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.
Topics: Adult; Anti-HIV Agents; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans; Zalcitabine; Zidovudine
PubMed: 10796851
DOI: 10.1002/14651858.CD002038 -
The Cochrane Database of Systematic... 2000Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection.... (Review)
Review
BACKGROUND
Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable.
OBJECTIVES
To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful induction therapy for HIV infection.
SEARCH STRATEGY
The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-1999 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity 2. AIDSLINE for the years 1982-1999 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamidvudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, Issue 2, 1999. 4. The specialist register of trials maintained by the Cochrane Collaborative Review Group on HIV Infection and AIDS 5. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. All reference lists of all review articles and primary articles identified were searched.
SELECTION CRITERIA
Randomized controlled trials in which HIV-infected adults who had successfully completed three- or four-drug antiretroviral induction therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful induction therapy was defined by a plasma viral load of less than 500 copies/ml.
DATA COLLECTION AND ANALYSIS
Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models.
MAIN RESULTS
Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using the same induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovuine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). (ABSTRACT TRUNCATED)
Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; Humans
PubMed: 10796850
DOI: 10.1002/14651858.CD002037