Carol A. Kemper

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response

OBJECTIVE To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING Five university-affiliated HIV clinics. PATIENTS A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION Individualized, unrestricted antiretroviral therapy. MEASUREMENTS Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

A Controlled Trial of Early Adjunctive Treatment with Corticosteroids for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome

BACKGROUND Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial. METHODS A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy. RESULTS Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms. CONCLUSIONS Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia.

Prophylaxis against Disseminated Mycobacterium avium Complex with Weekly Azithromycin, Daily Rifabutin, or Both

BACKGROUND Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy

BACKGROUND Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Effect of brief safer-sex counseling by medical providers to HIV-1 seropositive patients: a multi-clinic assessment.

Objective: To test the efficacy of brief, safer-sex counseling by medical providers of HIV-positive patients during medical visits. Setting: Six HIV clinics in California. Design: Clinics were randomized to intervention arms evaluated with cohorts of randomly selected patients measured before and after the intervention. Participants: Five-hundred and eighty-five HIV-positive persons, sexually active prior to enrollment. Interventions: Prevention counseling from medical providers supplemented with written information. Two clinics used a gain-framed approach (positive consequences of safer-sex), two used a loss-frame approach (negative consequences of unsafe sex), and two were attention-control clinics (medication adherence). Interventions were given to all patients who attended the clinics. Outcome measure: Self-reported unprotected anal or vaginal intercourse (UAV). Results: Among participants who had two or more sex partners at baseline, UAV was reduced 38% (P < 0.001) among those who received the loss-frame intervention. UAV at follow-up was significantly lower in the loss-frame arm [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.19–0.91; P = 0.03] compared with the control arm. Using generalized estimating equations (GEE) to adjust for clustering did not change the conclusions (OR, 0.34; 95% CI, 0.24–0.49; P = 0.0001). Similar results were obtained in participants with casual partners at baseline. No effects were seen in participants with only one partner or only a main partner at baseline. No significant changes were seen in the gain-frame arm. Conclusions: Brief provider counseling emphasizing the negative consequences of unsafe sex can reduce HIV transmission behaviors in HIV-positive patients presenting with risky behavioral profiles.

Visceral bacillary epithelioid angiomatosis: Possible manifestations of disseminated cat scratch disease in the immunocompromised host: A report of two cases

Opportunistic infection with the causative agent of cat scratch disease may be responsible for an unusual vascular proliferative lesion, referred to as bacillary epithelioid angiomatosis, previously described only in human immunodeficiency virus (HIV)-infected patients. We present a case of an HIV-infected patient with bacillary epithelioid angiomatosis involving the liver and bone marrow causing progressive hepatic failure. We also report a case of a cardiac transplant recipient with hepatic and splenic bacillary epithelioid angiomatosis manifesting as a fever of unknown origin, a previously unreported event in a non-HIV-infected patient. These cases represent the first documentation of bacillary epithelioid angiomatosis with visualization of cat scratch-like organisms involving internal organs.

Safety and Immunogenicity of Hepatitis A Vaccine in Human Immunodeficiency Virus-Infected Patients: A Double-Blind, Randomized, Placebo-Controlled Trial

The safety and immunogenicity of inactivated hepatitis A (HepA) vaccine was assessed in 133 hepatitis A virus-seronegative, human immunodeficiency virus (HIV)-infected adults. Patients were randomly assigned to receive, in a blinded fashion, either 2 doses of vaccine (1440 enzyme-linked immunosorbent assay units) or placebo 6 months apart. Seroconversion at month 9 was observed in 68% of those with CD4 cell counts >/=200 cells/mm(3) but in only 9% of those with lower CD4 cell counts (P=.004). HepA vaccine was well tolerated and had no effect on the course of HIV infection or plasma HIV RNA load.

Are HIV care providers talking with patients about safer sex and disclosure?: A multi-clinic assessment

Objectives: To examine HIV-positive patients’ reports of whether HIV care providers ever talked with them about practicing safer sex and disclosing seropositive status to sex partners. Design: Cross-sectional survey (1998–1999) of HIV-positive men and women sampled randomly at six public HIV clinics in California. Methods: Participants were interviewed and asked whether applicable clinic providers (physician, physician assistant, nurse practitioner, nurse, social worker, health educator, psychologist, psychiatrist) ever talked with them about safer sex or disclosure. Responses were analyzed by clinic site, HIV medical status (viral load), demographic, and behavioral variables (unprotected intercourse, non-disclosure). Results: The sample (n = 839) included heterosexual men (n = 127), men who have sex with men (MSM; n = 607), and women (n = 105). Thirty-nine percent were white, 36% Hispanic, 17% black, and 8% other/mixed ethnicity. Overall, 71% reported that an applicable provider had talked with them at least once about safer sex (range across clinics, 52–94%); 50% reported discussion of disclosure (range across clinics, 31–78%). Discussion of safer sex was more prevalent with physicians than with other clinic staff. In multivariate analyses, in addition to significant clinic differences, MSM (versus heterosexual men) and whites (versus blacks or Hispanics) were less likely to receive prevention messages on these topics. Patients’ behaviors (unsafe sex, non-disclosure) and HIV medical status were not independently associated with provider communication. Conclusions: HIV clinics differed substantially in the percentage of patients who reported that they received prevention messages from clinic staff. Care providers should assess and overcome barriers to providing prevention messages to patients.

Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Frontostriatal fiber bundle compromise in HIV infection without dementia

Background:Quantitative fiber tracking derived from diffusion tensor imaging (DTI) was used to determine whether white matter association, projection, or commissural tracts are affected in nondemented individuals with HIV infection and to identify the regional distribution of sparing and impairment of fiber systems. Methods:DTI measured fractional anisotropy and diffusivity, quantified separately for longitudinal (λL) diffusivity (index of axonal injury) and transverse (λT) diffusivity (index of myelin injury), in 11 association and projection white matter tracts and six commissural tracts in 29 men and 13 women with HIV infection and 88 healthy, age-matched controls (42 men and 46 women). Results:The total group of HIV-infected individuals had higher diffusivity (principally longitudinal) than controls in the posterior sectors of the corpus callosum, internal and external capsules, and superior cingulate bundles. High longitudinal diffusivity, indicative of axonal compromise, was especially prominent in posterior callosal sectors, fornix, and superior cingulate bundle in HIV with AIDS. Unmedicated patients had notably high transverse diffusivity, indicative of myelin compromise, in the occipital forceps, inferior cingulate bundle, and superior longitudinal fasciculus. Pontocerebellar projection fibers were resistant to HIV effects as were commissural fibers coursing through premotor and sensorimotor callosal sectors. Conclusion:This quantitative survey of brain fiber tract integrity indicates that even nondemented HIV patients can have neuroradiological evidence for damage to association and commissural tracts. These abnormalities were vulnerable to exacerbation with AIDS and possibly mitigated by HAART.