ABSTRACT
Cannabis species have been used as medicine for thousands of years; only since the 1940s has the plant not been widely available for medical use. However, an increasing number of jurisdictions are making it possible for patients to obtain the botanical for medicinal use. For the cancer patient, cannabis has a number of potential benefits, especially in the management of symptoms. Cannabis is useful in combatting anorexia, chemotherapy-induced nausea and vomiting, pain, insomnia, and depression. Cannabis might be less potent than other available antiemetics, but for some patients, it is the only agent that works, and it is the only antiemetic that also increases appetite. Inhaled cannabis is more effective than placebo in ameliorating peripheral neuropathy in a number of conditions, and it could prove useful in chemotherapy-induced neuropathy. A pharmacokinetic interaction study of vaporized cannabis in patients with chronic pain on stable doses of sustained-release opioids demonstrated no clinically significant change in plasma opiates, while suggesting the possibility of synergistic analgesia. Aside from symptom management, an increasing body of in vitro and animal-model studies supports a possible direct anticancer effect of cannabinoids by way of a number of different mechanisms involving apoptosis, angiogenesis, and inhibition of metastasis. Despite an absence of clinical trials, abundant anecdotal reports that describe patients having remarkable responses to cannabis as an anticancer agent, especially when taken as a high-potency orally ingested concentrate, are circulating. Human studies should be conducted to address critical questions related to the foregoing effects.
ABSTRACT
Cannabis has been used in medicine for thousands of years prior to achieving its current illicit substance status. Cannabinoids, the active components of Cannabis sativa, mimic the effects of the endogenous cannabinoids (endocannabinoids), activating specific cannabinoid receptors, particularly CB1 found predominantly in the central nervous system and CB2 found predominantly in cells involved with immune function. Delta-9-tetrahydrocannabinol, the main bioactive cannabinoid in the plant, has been available as a prescription medication approved for treatment of cancer chemotherapy-induced nausea and vomiting and anorexia associated with the AIDS wasting syndrome. Cannabinoids may be of benefit in the treatment of cancer-related pain, possibly synergistic with opioid analgesics. Cannabinoids have been shown to be of benefit in the treatment of HIV-related peripheral neuropathy, suggesting that they may be worthy of study in patients with other neuropathic symptoms. Cannabinoids have a favorable drug safety profile, but their medical use is predominantly limited by their psychoactive effects and their limited bioavailability.
Subject(s)
Cannabinoids/therapeutic use , Medical Marijuana/therapeutic use , Neoplasms/drug therapy , Analgesia , Analgesics, Opioid/pharmacology , Animals , Appetite/drug effects , Cannabinoids/adverse effects , Cannabinoids/pharmacology , Drug Interactions , Humans , Neoplasms/physiopathology , Pain, Intractable/drug therapy , Vomiting/drug therapyABSTRACT
Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.
Subject(s)
Analgesics, Opioid/therapeutic use , Chronic Pain/drug therapy , Dronabinol/pharmacology , Morphine/therapeutic use , Oxycodone/therapeutic use , Administration, Inhalation , Adult , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Area Under Curve , Delayed-Action Preparations , Dronabinol/adverse effects , Drug Administration Schedule , Drug Synergism , Female , Humans , Male , Middle Aged , Morphine/administration & dosage , Morphine/pharmacokinetics , Oxycodone/administration & dosage , Oxycodone/pharmacokinetics , Treatment OutcomeABSTRACT
Although cannabis may have potential therapeutic value, inhalation of a combustion product is an undesirable delivery system. The aim of the study was to investigate vaporization using the Volcano((R)) device as an alternative means of delivery of inhaled Cannabis sativa. Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a standard cigarette. One strength (1.7, 3.4, or 6.8% tetrahydrocannabinol (THC)) and delivery system was randomly assigned for each of the 6 study days. Plasma concentrations of Delta-9-THC, expired carbon monoxide (CO), physiologic and neuropsychologic effects were the main outcome measures. Peak plasma concentrations and 6-h area under the plasma concentration-time curve of THC were similar. CO levels were reduced with vaporization. No adverse events occurred. Vaporization of cannabis is a safe and effective mode of delivery of THC. Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system.
Subject(s)
Cannabinoids/administration & dosage , Nebulizers and Vaporizers , Volatilization , Administration, Inhalation , Adult , Area Under Curve , Carbon Monoxide/metabolism , Dronabinol/blood , Equipment Design , Female , Humans , Male , Marijuana Abuse , Marijuana Smoking , Middle Aged , Pilot ProjectsABSTRACT
OBJECTIVE: To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. METHODS: Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. RESULTS: Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. CONCLUSION: Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.
Subject(s)
Cannabis , HIV Infections/complications , Peripheral Nervous System Diseases/therapy , Peripheral Nervous System Diseases/virology , Phytotherapy , Sensation Disorders/therapy , Sensation Disorders/virology , Affect , Cannabis/adverse effects , Female , Hot Temperature , Humans , Hyperalgesia/physiopathology , Male , Middle Aged , Pain/physiopathology , Pain Management , Palliative Care , Peripheral Nervous System Diseases/physiopathology , Peripheral Nervous System Diseases/psychology , Physical Stimulation , Sensation Disorders/physiopathology , Sensation Disorders/psychology , SmokingABSTRACT
This manuscript extends our previously published work (based on data from one clinic) on the association between three drinking water-treatment modalities (boiling, filtering, and bottling) and diarrhoeal disease in HIV-positive persons by incorporating data from two additional clinics collected in the following year. We conducted a cross-sectional survey of drinking water patterns, medication usage, and episodes of diarrhoea among HIV-positive persons attending clinics associated with the San Francisco Community Consortium. We present combined results from our previously published work in one clinic (n = 226) with data from these two additional clinics (n = 458). In this combined analysis we employed logistic regression and marginal structural modelling of the data. The relative risk of diarrhoea for 'always' vs. 'never' drinking boiled water was 0.68 (95% CI 0.45-1.04) and for 'always' vs. 'never' drinking bottled water was 1.22 (95 % CI 0.82-1.82). Drinking filtered water was unrelated to diarrhoea (1.03 (95% CI 0.78, 1.35) for 'always' vs. 'never' drinking filtered water]. Adjustment for confounding did not have any notable effect on the point estimates (0.61, 1.35 and 0.98 for boiled, bottled, and filtered water respectively, as defined above). The risk of diarrhoea was lower among those consuming boiled water but this finding was not statistically significant. Because of these findings, the importance of diarrhoea in immunocompromised individuals, and the limitations of cross-sectional data further prospective investigations of water consumption and diarrhoea among HIV-positive individuals are needed.
Subject(s)
Diarrhea/epidemiology , Diarrhea/etiology , HIV Infections , Water Purification/methods , Adolescent , Adult , Aged , Aged, 80 and over , CD4 Lymphocyte Count , California/epidemiology , Child , Confounding Factors, Epidemiologic , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Medical Records , Middle Aged , Risk Factors , San Francisco/epidemiology , Water SupplyABSTRACT
To determine whether HIV infection, the wasting syndrome, or nucleoside analog reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) therapy uniquely affect fat distribution in men, we performed manual regional analysis of total, appendicular, trunk, and central abdominal fat measured by dual-energy X-ray absorptiometry (DEXA). Five groups of study subjects were identified for this cross-sectional analysis: HIV-negative controls (HIV-; N = 44) and four groups of HIV-positive subjects: antiretroviral (ARV)-naive or with limited prior use of NRTIs (ARV-; N = 23); on NRTIs for > or =6 months but PI-naive (NRTI; N = 30); on an NRTI/PI regimen for > or =6 months but with no complaints of abnormal fat distribution (NRTI/PI; N = 26); and those on NRTIs but PI-naive with the wasting syndrome (NRTI/WS; N = 40). Total, appendicular, trunk, and central abdominal fat was significantly lower in NRTI/WS. The ratio of trunk fat to appendicular fat was virtually identical in HIV- and ARV-. This ratio was significantly higher in the NRTI, NRTI/PI, and NRTI/WS groups, and values in these three groups were similar. These cross-sectional data suggest that HIV-infected men receiving NRTIs have an altered pattern of fat distribution, compared with HIV-negative men and HIV-positive men who are not receiving antiretroviral therapy. This effect was independent of the concomitant use of a PI or a diagnosis of the wasting syndrome. We saw no evidence of a unique effect of HIV infection per se on regional fat distribution. Although the fat ratio is increasingly employed, its physiologic significance is unclear. Our results, which have been obtained retrospectively, are intended to provide the impetus for prospective, controlled studies of the interactions among drug and host factors in the development of fat distribution abnormalities.
Subject(s)
Adipose Tissue/metabolism , Anti-HIV Agents/adverse effects , Body Composition , HIV Infections/drug therapy , HIV-1 , Reverse Transcriptase Inhibitors/adverse effects , Adult , Cross-Sectional Studies , HIV Protease Inhibitors/adverse effects , HIV Wasting Syndrome , Humans , Male , Retrospective StudiesABSTRACT
Although the HIV wasting syndrome has become a far less common manifestation of advanced disease since the introduction of highly active therapies, much has been learned about a number of potential therapeutic interventions. HIV wasting therapies are reviewed. The evaluation of some of these treatments for management of body habitus alterations associated with antiretroviral therapies may be appropriate.
Subject(s)
Anabolic Agents/therapeutic use , Anti-HIV Agents/therapeutic use , Appetite Stimulants/therapeutic use , HIV Wasting Syndrome/drug therapy , Thalidomide/therapeutic use , Clinical Trials as Topic , Female , Humans , MaleABSTRACT
To evaluate the effect of epoetin alfa on the quality of life (QOL) of HIV-infected patients in the community setting, 221 anaemic (haemoglobin < or = 11 g/dl) HIV-positive patients from community-based treatment centres and physicians' offices were treated with epoetin alfa (100-300 units/kg subcutaneously 3 times a week) in a 4-month, open-label, non-randomized, phase IV trial. Epoetin alfa therapy significantly (P<0.01) increased and maintained haemoglobin levels (mean increase=2.5 g/dl; n=207); the improvement in haemoglobin levels was independent of changes in CD4+ cell counts. Transfusion requirements were also significantly reduced from 20% to 5% of patients (P<0.01). Mean total QOL score measured by the Functional Assessment of HIV Infection (FAHI) scale and Physical Well-Being subscale score improved significantly (P<0.05). QOL improvements associated with increases in haemoglobin were independent of changes in CD4+ counts and baseline anaemia severity. Adverse events observed during epoetin alfa therapy were consistent with HIV disease and not likely due to the drug. Epoetin alfa therapy should be considered a treatment option for HIV-infected patients with mild-to-moderate anaemia.
Subject(s)
Anemia/prevention & control , Erythropoietin/therapeutic use , HIV Infections/drug therapy , Hematinics/therapeutic use , Adult , Anemia/blood , Epoetin Alfa , Female , HIV Infections/blood , HIV Infections/complications , Hemoglobins/analysis , Humans , Male , Quality of Life , Recombinant ProteinsABSTRACT
OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.
Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/therapeutic use , Drug Resistance, Microbial/genetics , HIV Infections/drug therapy , HIV-1/genetics , Acquired Immunodeficiency Syndrome/blood , Acquired Immunodeficiency Syndrome/immunology , Adult , CD4 Lymphocyte Count , Drug Therapy, Combination , Female , Genotype , HIV Infections/blood , HIV Infections/immunology , HIV Protease Inhibitors/therapeutic use , HIV Reverse Transcriptase/genetics , HIV-1/isolation & purification , Humans , Male , Mutation , RNA, Viral/blood , RNA, Viral/genetics , Viral LoadABSTRACT
OBJECTIVES: To test the hypothesis that Kaposi's sarcoma (KS) protects against four central nervous system (CNS) diseases in HIV-1-infected individuals. STUDY POPULATION AND DESIGN: The study population of 9404 subjects included participants in Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) protocols who were enrolled between September 1990 and September 1998. This was an observational study. METHODS: Proportional hazards regression was used to estimate adjusted relative risks for predictors of four central nervous system diseases. Covariates included occurrence of Kaposi's sarcoma, occurrence of other opportunistic infections or malignancies, baseline CD4+ count, and other baseline characteristics. RESULTS: Among the 5944 participants without progression to AIDS at entry, 451 developed a CNS disease. The adjusted relative risk of any CNS disease for those who developed Kaposi's sarcoma versus those who did not develop any AIDS-defining event was 1.41 [95% confidence interval (CI), 0.98-2.03; P = 0.06]. In contrast, the adjusted relative risk of any CNS disease for those with Kaposi's sarcoma versus those with some other non-Kaposi's sarcoma AIDS-defining event was 0.37 (95% CI, 0.24-0.57; P < 0.0001). Among the 3460 participants with progression to AIDS at entry, the adjusted relative risk of any CNS disease for those with Kaposi's sarcoma versus those with some other non-Kaposi's sarcoma AIDS-defining event was 0.71 (95% CI, 0.40-1.25; P = 0.23). CONCLUSIONS: Our analyses indicate that the risk of CNS disease associated with Kaposi's sarcoma depends strongly on the reference or control group chosen. When compared to individuals with other non-Kaposi's sarcoma AIDS-defining diseases, Kaposi's sarcoma is associated with a lower risk of CNS disease in HIV-1 positive individuals. However, when compared to individuals with no AIDS-defining disease or with a similarly mild AIDS-defining disease such as invasive candidiasis, Kaposi's sarcoma is associated with an equivalent risk of CNS disease.
Subject(s)
AIDS-Related Opportunistic Infections/complications , Central Nervous System Diseases/complications , HIV Infections/complications , Sarcoma, Kaposi/complications , AIDS Dementia Complex/complications , Adult , Female , Humans , Leukoencephalopathy, Progressive Multifocal/complications , Lymphoma, AIDS-Related/immunology , Male , Middle Aged , Proportional Hazards Models , Risk Factors , Toxoplasmosis, Cerebral/complicationsABSTRACT
To determine if providers experienced in the management of human immunodeficiency virus (HIV) disease preferred different treatment regimens than providers with less experience, we analyzed data from a national survey of primary care providers' preferred regimens for the management of 30 HIV-related medical conditions. We mailed questionnaires to 999 correct addresses of providers in > 20 cities in the United States in May 1996. We received 524 responses (response rate, 52%). We found a statistically significant association between the number of HIV-infected patients cared for by the provider and the likelihood that the provider would report prescribing highly active antiretroviral therapy and multidrug combinations for treatment of opportunistic infections. Providers with few HIV-infected patients were substantially less likely to report using new therapeutic regimens or new diagnostic tools. We concluded that the preferred regimens of experienced providers are more likely to be consistent with the latest information on treatment for HIV disease than are those of less experienced providers.
Subject(s)
AIDS-Related Opportunistic Infections/drug therapy , Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Practice Patterns, Physicians' , Primary Health Care , AIDS-Related Opportunistic Infections/prevention & control , Drug Therapy, Combination , Family Practice , HIV Infections/complications , Health Care Surveys , HumansABSTRACT
Community-based AIDS research programs were initially federally funded in 1989. Since then, the Terry Beirn Community Programs for Clinical Research on AIDS has mandated that research units develop and maintain community advisory boards to provide advice and communicate community preferences in AIDS research. Seventeen community-based AIDS research units formed community advisory boards (CABs) based on a model developed by the Community Consortium at San Francisco General Hospital. Social workers employed by these AIDS research units surveyed 267 CAB members to ascertain board characteristics and members' perceptions of program activities. Implications for social work and future research are discussed.
Subject(s)
Acquired Immunodeficiency Syndrome , Clinical Trials as Topic/standards , Community Health Services/organization & administration , Community Participation , Social Work , Female , Humans , Male , San Francisco , Surveys and QuestionnairesABSTRACT
Widespread use of smoked marijuana in the San Francisco Bay Area as a treatment for HIV-related anorexia and weight loss, as well as nausea related to prescribed therapy, prompted the design of a clinical trial to evaluate the safety and effectiveness of this controlled substance. The Community Consortium--the Bay Area's community-based HIV clinical trials organization--designed a first pilot evaluation of smoked marijuana compared to oral tetrahydrocannabinol (THC, synthesized as dronabinol or Marinol) in 1993. A legal source of marijuana could not be identified. Two subsequent applications to the National Institutes of Health were submitted in 1996 and 1997. During the intervening period, increasing numbers of people with HIV infection were obtaining marijuana for "medicinal use" from local Cannabis Buyer's Clubs. In November 1996, California voters endorsed the medical use of marijuana by approving Proposition 215. The federal government's attempt to oppose the voters' mandate led to public outrage. Organized medicine demanded more studies into marijuana's potential use as medicine. The consortium's 1997 proposal to evaluate the potential interaction between THC and widely-prescribed protease inhibitors was positively received. Funding and study-required marijuana cigarettes have been obtained from the National Institute of Drug Abuse, and the first subjects are being enrolled in the trial. When politically sensitive research proposals include sound science, they can prevail if investigators are willing to persist.
Subject(s)
Cannabis/therapeutic use , HIV Wasting Syndrome/therapy , Phytotherapy , Clinical Trials as Topic , Humans , Pilot Projects , San FranciscoABSTRACT
Severe weight loss in HIV is associated with decreased length of survival. It is unclear whether mild weight loss is associated with an increased risk of death or opportunistic complications of HIV. Participants in four interventional studies (n = 2382) conducted by a community-based clinical trials network were evaluated for percentage change in weight during their first 4 months in the study. Proportional hazards models were performed for the occurrence of opportunistic complications and death subsequent to the 4-month visit. The relative risk of death and opportunistic complications for those with 5% to 10% weight loss over 4 months was 2.22 (p < .001) and 1.89 (p < .001), respectively, and 1.26 (p < .01) and 1.19 (p < .01) among those who lost 0% to 5% of their body weight, respectively, when compared with those with no weight loss. Among those who lost 5% to 10% of their body weight, the relative risk of individual opportunistic complications increased significantly, including Pneumocystis carinii pneumonia (PCP) (1.61; p < .01), cytomegalovirus (CMV) (2.33; p < .001), and Mycobacterium avium complex (MAC) (1.81; p < .01). As little as 5%t weight loss over a 4-month period is associated with increased risk of death and opportunistic complications in HIV. A weight loss of 5% to 10% is also associated with an increased risk of individual opportunistic complications.
Subject(s)
AIDS-Related Opportunistic Infections/epidemiology , HIV Infections/physiopathology , Weight Loss , Adult , Cohort Studies , Disease Progression , Female , Follow-Up Studies , HIV Infections/mortality , Humans , Male , Middle Aged , Risk Factors , Survival AnalysisABSTRACT
This report of a 1995 survey presents data regarding nurses' attitudes and beliefs about assisted suicide in AIDS. The authors surveyed 428 nurses working at facilities serving AIDS patients in the San Francisco Bay Area, using an anonymous, self-administered questionnaire. They received 215 responses (50%). There was a high level of agreement with statements that place assisted suicide in the context of humane action to relieve suffering. An AIDS diagnosis did not change respondents' attitudes toward assisted suicide, although many nurses said that the relentless suffering and specific nature of the AIDS epidemic did influence their thinking.
Subject(s)
Acquired Immunodeficiency Syndrome , Attitude of Health Personnel , Nurses/psychology , Suicide, Assisted/psychology , Acquired Immunodeficiency Syndrome/nursing , Acquired Immunodeficiency Syndrome/psychology , Attitude to Death , Educational Status , Ethics, Nursing , Female , Humans , Male , Religion and Medicine , San Francisco , Surveys and QuestionnairesABSTRACT
OBJECTIVE: Evaluate safety and efficacy of oral ganciclovir (GCV) for preventing cytomegalovirus (CMV) disease in HIV-infected persons at high risk for CMV disease. DESIGN: Double-blind, placebo-controlled, randomized clinical trial in primary care clinics and private practice offices specializing in the care of people with HIV. Interventions were oral GCV (1000 mg three times/day) or placebo. Protocol amendment allowed switch to open-label oral GCV. Main outcome measures were confirmed CMV retinal or gastrointestinal mucosal disease, and death. The study enrolled 994 people co-infected with CMV and HIV, with at least one CD4 count recorded < 100 x 10(6) cells/l. RESULTS: At study completion (15 months median follow-up), CMV event rates in the oral GCV and control groups were 13.1 and 14.6 per 100 person years, respectively, a hazard ratio (HR) of 0.92 [95% confidence interval (CI), 0.65-1.27; P = 0.6]. At protocol amendment event rates were 12.7 and 15.0, respectively (HR, 0.85; 95% CI, 0.56-1.30; P = 0.45). At study completion, event rates for death were 26.6 and 32.0 (HR, 0.84; P = 0.09), and at protocol amendment were 18.9 and 19.6 (HR, 0.95; P = 0.78), respectively. At protocol amendment for the CMV endpoint, the oral GCV treatment effect was associated with baseline use of didanosine (ddI). For patients taking ddI at randomization, HR was 7.48 (P = 0.02). For patients not taking ddI, HR was 0.62 (P = 0.04). These HR were statistically different (P = 0.0006). CONCLUSIONS: In our study, 3 g/day oral GCV did not significantly reduce CMV disease incidence, but there was a suggestion of a death-rate reduction. Furthermore, results suggest that oral GVC decreased risk of CMV disease in patients not prescribed ddI, and increased risk in those prescribed ddI. For the CMV endpoint, our study differs markedly from the only similar study, although for the death endpoint, a combined analysis of studies indicated significant reduction in death rate.