Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030.

PURPOSE: To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia. METHODS: Subjects (N = 338) were HIV-infected with CD4+ count <100 cells/mm3, plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2). RESULTS: Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. During Step 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months. CONCLUSIONS: We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population.

Human immunodeficiency virus infection of human-PBL-SCID mice.

Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) have inducible human immune function and may be useful as a small animal model for acquired immunodeficiency syndrome (AIDS) research. Hu-PBL-SCID mice infected with human immunodeficiency virus-1 (HIV-1) contained virus that was recoverable by culture from the peritoneal cavity, spleen, peripheral blood, and lymph nodes for up to 16 weeks after infection; viral sequences were also detected by in situ hybridization and by amplification with the polymerase chain reaction (PCR). Mice could be infected with multiple strains of HIV-1, including LAV-1/Bru, IIIB, MN, SF2, and SF13. HIV-1 infection affected the concentration of human immunoglobulin and the number of CD4+ T cells in the mice. These results support the use of the hu-PBL-SCID mouse for studies of the pathogenesis and treatment of AIDS.

Poor outcome is associated with delayed tuberculosis diagnosis in HIV-infected children in Baja California, Mexico.

OBJECTIVE: To describe the morbidity and mortality associated with tuberculosis (TB) in human immunodeficiency virus (HIV) infected children in Baja California, Mexico. METHODS: Retrospective review of the medical records of all children with perinatally acquired HIV infection evaluated at Tijuana General Hospital with a diagnosis of TB between 1998 and 2007. The Stegen-Toledo (ST) clinical criteria for the diagnosis of TB were used. RESULTS: A total of 73 HIV-infected children were followed during the study period. Thirteen (18%) children were diagnosed with TB; one was confirmed by culture to be positive. Among these children, the mean ages at HIV and TB diagnosis were respectively 3.6 and 5.3 years. The mean ST score was 8.1; 10/13 had a score of >or=7, or highly probable TB. There were a cumulative 29 hospital admissions prior to TB diagnosis; 24 of these were due to pneumonia. The mean duration of symptoms at TB diagnosis was 73 days. The most common symptoms were cough (92%) and anorexia (85%). Seven patients (54%) had disseminated TB and five (39%) died as a consequence of TB. CONCLUSIONS: We observed high morbidity, hospital utilization and high mortality associated with TB among HIV-infected children in Baja California.

Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients.

In this study, baseline plasma from 619 persons with acquired immunodeficiency syndrome (AIDS) (median CD4+ lymphocyte count -21/microl) who participated in a trial to determine the efficacy of oral ganciclovir for cytomegalovirus (CMV) disease prevention were evaluated for CMV DNA load by qualitative and quantitative polymerase chain reaction (PCR), and correlated with the development of CMV disease and survival. For participants without detectable plasma CMV DNA, the 12-mo Kaplan-Meier CMV disease event rate was 14% and 1% for the placebo and ganciclovir groups, respectively (P < 0.001). For PCR positive participants, CMV disease developed in 43% of placebo and 26% ganciclovir recipients (P < 0.017). Among placebo recipients, CMV PCR positivity was associated with a 3.4-fold increased risk of developing CMV disease (P < 0.001) whereas CD4+ lymphocyte count was not a useful predictor (P = 0.47). A positive plasma CMV DNA PCR was also associated with a 2.5-fold increased risk of death. Each log10 increase in baseline CMV DNA load was associated with a 3.1-fold increase in CMV disease (P < 0.001) and a 2.2-fold increase in mortality (P < 0.001). These data indicate that the risk of developing CMV disease and death in persons with advanced AIDS is directly related to the quantity of CMV DNA in plasma, and is a better predictor than CD4+ lymphocyte count in this population.

Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma.

Specific mutations in the UL97 region of human cytomegalovirus (HCMV) have been found to confer resistance to laboratory-adapted strains subjected to ganciclovir selection. In this study, mutations in the UL97 region of HCMV isolates obtained from patients receiving ganciclovir therapy were examined to determine whether they would confer ganciclovir resistance, and if these mutations could be detected directly in the plasma of AIDS patients with progressive HCMV disease despite ganciclovir treatment. A single nucleotide change within a conserved region of UL97 was found in five resistant isolates, resulting in an amino acid substitution in residue 595: from leucine to phenylalanine in one, and from leucine to serine in four resistant isolates. A sixth resistant isolate demonstrated a single nucleotide change, leading to a threonine to isoleucine substitution in residue 659. The role of the 595 amino acid substitution in conferring ganciclovir resistance was confirmed by marker transfer experiments. In further studies, direct sequencing of HCMV DNA present in plasma obtained from persons with resistant viruses revealed the identical amino acid substitutions in plasma as those present in the cultured viruses. These findings indicate that clinical resistance to ganciclovir can result from specific point mutations in the UL97 gene, and that the emergence of the resistant genotype can be detected directly in patient plasma.

Prevalence of primary HIV-1 drug resistance in pregnant women and in newly diagnosed adults at Tijuana General Hospital, Baja California, Mexico.

At Tijuana General Hospital, between March 2003 and June 2005, pregnant women and other adults, recently identified as HIV infected, antiretroviral naïve, were enrolled to examine the prevalence of primary HIV drug resistance. All subjects had the Calypte HIV-1 BED Incidence enzyme immunoassay test to identify recent infection. Genotypic analysis of HIV-1 protease and reverse transcriptase regions in plasma was performed. Forty-six subjects participated, eight (17%) men, 38 (83%) women. Ten (22%) subjects were classified as having recent HIV infection. HIV genotype was performed in 41 subjects. One subject (2.5%) had a major mutation in the reverse transcriptase region (K219Q) conferring zidovudine resistance, one had a minor mutation at V118I (2.5%) and two subjects (5%) had minor mutation (V179D) associated with non-nucleoside reverse transcriptase inhibitor resistance. There were no major protease inhibitor-associated mutations but minor mutations were common. The prevalence of primary HIV drug resistance in Baja California is low.

Performance of rapid HIV testing using Determine HIV-1/2 for the diagnosis of HIV infection during pregnancy in Tijuana, Baja California, Mexico.

The aim of this study was to evaluate the performance of the rapid antibody test Determine HIV-1/2, in pregnant women at Tijuana General Hospital. Pregnant women seeking prenatal care or admitted in labour had blood drawn for a rapid HIV test (Determine HIV-1/2), enzyme immunoassay (EIA) and Western blot. Between March and November 2003, 1068 women in labour and 1529 women in prenatal care were enrolled. The sensitivity, specificity, positive and negative predictive values were 100%, 99.8%, 77% and 100%, respectively. For women in labour, the mean time between blood collection and rapid test results was 92 minutes (range: 20-205 minutes) compared with 41 hours (range 24-120 hours) for HIV EIA (P = 0.012). All HIV-exposed infants received oral zidovudine. These findings indicate that the rapid test Determine HIV-1/2 has a high sensitivity and specificity in pregnant women. Rapid HIV testing greatly diminishes the time to diagnosis and enables prompt intervention with antiretrovirals at delivery.

Newborn Hearing Screenings in Human Immunodeficiency Virus-Exposed Uninfected Infants.

Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.

The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy.

BACKGROUND: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). METHOD: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. RESULTS: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. CONCLUSION: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

Search for cytomegalovirus in the postmortem brains of schizophrenic patients using the polymerase chain reaction.

Cytomegalovirus infection has a number of features that suggest a possible association between congenital infection and schizophrenia. Previous studies have investigated anticytomegalovirus antibody titers or attempted directly to identify viral antigens in body fluids or brain tissue from schizophrenic subjects but have been limited by the sensitivity of the available methods. The highly sensitive polymerase chain reaction, a newly developed technique for gene amplification, was used to search for cytomegalovirus in the DNA extracted from postmortem temporal cortex samples of eight schizophrenic subjects, eight nonschizophrenic suicide victims, and eight normal controls. Cytomegalovirus-specific DNA amplification was not detected in any of the samples. The implications of this finding for the viral hypothesis of schizophrenia are discussed.

Prevalence of psychiatric disorders among men infected with human immunodeficiency virus. A controlled study.

We used structured diagnostic interviews and rating scales to assess lifetime prevalence of psychiatric disorders, by DSM-III criteria, among an unselected sample of 56 ambulatory homosexual men in four groups: men with acquired immunodeficiency syndrome (AIDS), men with AIDS-related complex (ARC), men asymptomatic or mildly symptomatic but seropositive for antibody to human immunodeficiency virus (HIV), and HIV-seronegative men. An age- and demographically matched comparison group of 22 healthy, heterosexual controls was also studied. The homosexual men had lifetime rates of alcohol or nonopiate drug abuse (22/56 [39.3%]), generalized anxiety disorder (22/56 [39.3%]), and major depression (17/56 [30.3%]) that often preceded diagnosed medical illness or knowledge of HIV status. The six-month point prevalence of these disorders in homosexual men was also high, especially alcohol abuse in patients with AIDS-related complex, and the occurrence of a DSM-III disorder within the previous six months significantly exceeded that in heterosexual controls. The data suggest that there may be a higher prevalence of anxiety disorder and major depressive illness in homosexual men when compared with sociodemographically matched heterosexual men and that the psychiatric morbidity may have preceded the onset of the AIDS epidemic. These findings indicate that awareness of psychiatric history is necessary to comprehensive medical care of men at high risk for AIDS, even among relatively healthy outpatients.

Dysregulation of cytokine expression in monocytes from HIV-positive individuals.

Because HIV may alter the production of inflammatory factors produced by monocytes, the expression of tumor necrosis factor alpha (TNF-alpha), tissue factor (TF), interleukin (IL)-1 beta, and IL-6 was evaluated in 47 HIV-seropositive persons and seronegative control subjects. RNA was extracted from freshly isolated lipopolysaccharide (LPS)-stimulated or unstimulated monocytes. Cytokine and TF expression was quantitated by dot blot hybridization or a reverse transcription polymerase chain reaction (RT-PCR). A significant depression of TF mRNA was observed in LPS-stimulated monocytes (66% less in AIDS, 20% less in AIDS-related complex (ARC), and 0% less in asymptomatic patients), whereas normal responses were observed for TNF-alpha, IL-1 beta, and IL-6. When constitutive expression was measured in unstimulated monocytes by RT-PCR, a differential pattern was also observed. TNF-alpha and IL-1 beta were positive in 85% of asymptomatic persons, compared with only 27% of ARC and 42% of AIDS patients. Expression of IL-6 was observed in lower proportions, 27-30%, with no significant differences among disease states. All samples were negative for TF. Thus, the regulation of inflammatory molecules is differentially altered in individuals with HIV infection. TF is preferentially down-regulated, compared with TNF-alpha, IL-1 beta, and IL-6, in LPS-stimulated monocytes as patients progress to AIDS. TNF-alpha and IL-1 beta are preferentially up-regulated, compared with IL-6 and TF, in unstimulated monocytes in asymptomatic persons, with a loss of up-regulation as patients progress to AIDS.

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.

HIV therapy advances. Pediatric antiretroviral choices.

BACKGROUND: Zidovudine is the initial treatment of choice in HIV-infected children. Zalcitabine or didanosine may be used in children who do not respond adequately or who are intolerant of zidovudine. Several studies of the latter agents are reviewed. MONOTHERAPY STUDIES: Zalcitabine at 0.005 or 0.01 mg/kg three times a day was associated with stabilization of growth and a decline in p24 antigen levels in more than 50% of treated children. In a dose-ranging study of didanosine, 30% of children showed an increase in CD4 cell counts and gained weight. There was a correlation between the plasma didanosine concentration and an improvement in IQ (Intelligence Quotient) and p24 status. STUDIES ON COMBINATION THERAPY: In a 12-18 month trial of zidovudine/zalcitabine in 13 children, most gained weight and more than half showed improved CD4 cell counts. The combination of various doses of didanosine with zidovudine was associated with a reduction in viral titer, a significant increase in CD4 cell counts and a trend towards increased weight in many children. STUDY IN MOTHER TO INFANT TRANSMISSION: Zidovudine or placebo was administered to women throughout pregnancy and during labor and to their new-born infants up to 6 weeks of age. The infection rate for the zidovudine-treated group was 8.3% compared with 25.5% for the placebo group (P = 0.000056). CONCLUSION: Zalcitabine and didanosine are useful drugs in the treatment of HIV-infected children. Zidovudine is associated with a reduced rate of mother to infant viral transmission.

HIV-induced apoptosis of activated primary CD4+ T lymphocytes is not mediated by Fas-Fas ligand.

OBJECTIVE: To investigate the role of the Fas-Fas ligand (FasL) interaction in HIV-1-induced apoptosis of primary CD4+ T lymphocytes. DESIGN: Activated CD4+ T lymphocytes are the main target of HIV, and T-cell activation leads to the expression of Fas-FasL and enhances HIV-mediated apoptosis. Phytohemagglutinin-activated primary CD4+ T cells were infected with HIV; the process of cell death was examined, and whether the dying and dead cells were the productively infected cells. The modulation of Fas and FasL expression and its role in HIV-induced cell death was also investigated. METHODS: The number of viable and dead cells was determined by trypan blue exclusion. Apoptosis was quantified using an enzyme-linked immunosorbent assay measuring the release of cytoplasmic histone-associated DNA fragments. The percentage of HIV-infected cells was determined by FACS analysis, and viral production was assessed by a p24 core antigen assay. The following three markers, HIV-gp-120, annexin-V and 7-AAD, were used to monitor the apoptotic process in HIV-negative and positive cells. Fas and FasL expression was analyzed at the RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. The contribution of Fas-FasL interactions to apoptosis was examined by blocking experiments using the antagonist ZB4 anti-Fas antibody. RESULTS: HIV-induced apoptosis in activated purified CD4+ T lymphocytes required infectious virus and was dose-dependent. Apoptosis in HIV-infected cultures was mostly confined to productively infected cells. The expression of Fas and FasL was not significantly modulated by infection and blocking Fas-FasL interactions did not reduce the extent of apoptosis. CONCLUSIONS: HIV-induced apoptosis of activated CD4+ T cells in vitro is confined to productively infected cells and is not mediated by a Fas-FasL interaction.

Diagnosis of cytomegalovirus infection.

The diagnosis of cytomegalovirus (CMV) infection in bone marrow transplant recipients is most accurately accomplished by the identification of CMV in the organ of concern; identification of CMV in bronchoalveolar lavage fluid can also be helpful in diagnosing CMV interstitial pneumonia. When tissue specimens are available, the identification of cytomegalic cells is often helpful in establishing CMV as the pathogen. Immunocytochemistry and in situ hybridization can increase the sensitivity and specificity of the CMV diagnosis; when nonisotopic detection systems are used, each can be performed the same day the specimen is obtained. Direct viral culture can also be used to establish a diagnosis. Although culture of CMV on human fibroblasts is still considered the diagnostic "gold standard," identification of the virus in culture may take several days to several weeks. The use of the shell-vial viral culture procedure, in conjunction with monoclonal antibodies directed at immediate early CMV antigens, has made it possible to detect CMV in culture within 24 hours. The use of nucleic acid hybridization procedures, including amplification of CMV sequences by the polymerase chain reaction, is highly sensitive; however, the application of these hybridization procedures to the diagnosis of CMV disease remains unclear.

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus.

To ascertain whether combination therapy with zidovudine (AZT) and zalcitabine (ddC) delayed the emergence of AZT resistance, isolates of human immunodeficiency virus (HIV) were evaluated from 15 previously untreated patients with advanced HIV disease who received combination therapy. Eighteen sequential viral isolates were available from 15 patients who received > or = 6 months of combination therapy. Isolates from eight (73%) of 11 patients obtained between 24 and 48 weeks of therapy were AZT resistant [50% inhibitory concentration (IC50) > or = 0.45 microM; range, 0.45-2.0 microM]. Four of these eight patients yielded virus isolates that were highly AZT resistant (IC50 > 1.0 microM). No changes in ddC susceptibility were discerned. The median IC50 for ddC was 0.2 microM and ranged from 0.07 to 0.5 microM. The CD4 cell counts of patients with AZT-sensitive virus tended to have higher median areas under the curve (AUC) and greater increases compared with patients who had AZT-resistant virus. They also had higher means and ranges of the average CD4 cell counts at week 36 (p = 0.01) and week 48 (p = 0.04). These data would indicate that the previously described more sustained CD4 cell responses conferred by the addition of ddC to AZT therapy cannot be ascribed to delayed emergence of AZT resistance with combination therapy.

Peripheral nerve function in persons with asymptomatic or minimally symptomatic HIV disease: absence of zidovudine neurotoxicity.

Nucleoside-induced neuropathy characteristically appears as a painful, symmetric, distal polyneuropathy. To evaluate the neurotoxic potential of zidovudine (ZDV, or azidothymidine), in persons with little confounding human immunodeficiency virus (HIV) neuropathy, we evaluated peripheral nerve function in persons completing placebo-controlled studies of ZDV in early HIV disease. Participants had been receiving placebo or ZDV at doses of 800-1,200 mg daily for a median 52 weeks at the time of evaluation. Neuropathic symptoms and abnormalities of motor and sensory function were present in fewer than 10% of both treatment groups. Depressed reflexes were found in 19% of the ZDV group and 18% of the placebo group. Quantitative sensory testing for vibration was abnormal in fewer than 10% of participants and the absolute scores favored the ZDV group. We thus found a low prevalence of peripheral nerve abnormalities and no evidence of ZDV neurotoxicity in this population.

Functional status and well-being in a placebo-controlled trial of zidovudine in early symptomatic HIV infection.

To determine the effect of zidovudine on functional status and well-being in patients with early symptomatic human immunodeficiency virus (HIV) infection, 70 subjects in a randomized, placebo-controlled trial (ACTG Protocol 016) were observed for 1 year using a brief quality-of-life questionnaire. Thirty-four subjects were assigned to placebo and 36 subjects to zidovudine, 200 mg orally every 4 h (1,200 mg daily). Functional status and well-being were measured every 3 months using a 30-item self-administered questionnaire derived from health ratings from the Medical Outcomes Study. The mean changes from baseline for zidovudine versus placebo groups were compared using paired and two-sample t tests. Subjects receiving a placebo reported better quality of life compared to baseline than subjects receiving zidovudine at 24 weeks for all dimensions of well-being, including overall health, energy, mental health, health distress, pain, and quality of life. The difference between the two groups' changes from baseline for overall health was 11.5 points on a 100-point scale (p = 0.02), and 11.1 points for energy (0.002). There were no differences between changes from baseline along various dimensions of functional status (physical, social, role, and cognitive function). At 52 weeks both groups reported worse overall health than at baseline, and changes in scores were more similar for the two groups. Although zidovudine has previously been demonstrated to delay progression of disease for patients with mildly symptomatic HIV infection, early in treatment the net effect of a 1,200 mg daily dose of zidovudine may diminish patients' subjective well-being.(ABSTRACT TRUNCATED AT 250 WORDS)