Richard Lalonde

A Comparison of Two Regimens for the Treatment of Mycobacterium avium Complex Bacteremia in AIDS: Rifabutin, Ethambutol, and Clarithromycin versus Rifampin, Ethambutol, Clofazimine, and Ciprofloxacin

BACKGROUND Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

Persistence and Fitness of Multidrug-Resistant Human Immunodeficiency Virus Type 1 Acquired in Primary Infection

ABSTRACT This study examines the persistence and fitness of multidrug-resistant (MDR) viruses acquired during primary human immunodeficiency virus infection (PHI). In four individuals, MDR infections persisted over the entire study period, ranging from 36 weeks to 5 years, in the absence of antiretroviral therapy. In stark contrast, identified source partners in two cases showed expected outgrowth of wild-type (WT) virus within 12 weeks of treatment interruption. In the first PHI case, triple-class MDR resulted in low plasma viremia (1.6 to 3 log copies/ml) over time compared with mean values obtained for an untreated PHI group harboring WT infections (4.1 to 4.3 log copies/ml). Increasing viremia in PHI patient 1 at week 52 was associated with the de novo emergence of a protease inhibitor-resistant variant through a recombination event involving the original MDR virus. MDR infections in two other untreated PHI patients yielded viremia levels typical of the untreated WT group. A fourth patients MDR infection yielded low viremia (<50 to 500 copies/ml) for 5 years despite his having phenotypic resistance to all antiretroviral drugs in his treatment regimen. In two of these PHI cases, a rebound to higher levels of plasma viremia only occurred when the M184V mutation in reverse transcriptase could no longer be detected and, in a third case, nondetection of M184V was associated with an inability to isolate virus. To further evaluate the fitness of MDR variants acquired in PHI, MDR and corresponding WT viruses were isolated from index and source partners, respectively. Although MDR viral infectivity (50% tissue culture infective dose) was comparable to that observed for WT viruses, MDR infections in each case demonstrated 2-fold and 13- to 23-fold reductions in p24 antigen and reverse transcriptase enzymatic activity, respectively. In dual-infection competition assays, MDR viruses consistently demonstrated a marked replicative disadvantage compared with WT virus. These results indicate that MDR viruses that are generated following PHI can establish persistent infections as dominant quasispecies despite their impaired replicative competence.

The impact of hepatitis C virus coinfection on HIV progression before and after highly active antiretroviral therapy.

To compare the impact of hepatitis C virus (HCV) coinfection on progression of HIV infection in the eras before and after the introduction of highly active antiretroviral therapy (HAART), the authors conducted a retrospective cohort study. One hundred twenty-five HCV+ patients and 1076 HCV- patients were studied; 83% of HCV+ patients were injection drug users. HCV+ subjects experienced no clear benefit from HAART. The adjusted hazard ratios (HRs) of opportunistic infection, death, and hospitalization were 0.74 (95% CI: 0.31-1.78), 1.78 (95% CI: 0.59-5.37), and 2.1 (95% CI: 0.90-4.90), respectively, comparing the post-HAART era with the pre-HAART era. In contrast, HCV- subjects experienced rate reductions for all outcomes. Comparable HRs for opportunistic infection, death, and hospitalization were 0.49 (95% CI: 0.37-0.64), 0.28 (95% CI: 0.19-0.41), and 0.51 (95% CI: 0.38-0.67), respectively. HCV+ subjects remained at increased risk for death and hospitalization post-HAART even after additional adjustment for antiretroviral use and time-updated CD4 cell and viral load measures. Deaths and hospitalizations in HCV+ patients were primarily for non-AIDS-defining infections and complications of injection drug use. HCV coinfection and comorbidity associated with injection drug use are preventing the realization of substantial health benefits associated with HAART.

Comparative Evaluation of the Cytomegalovirus DNA Load in Polymorphonuclear Leukocytes and Plasma of Human Immunodeficiency Virus-Infected Subjects

The cytomegalovirus (CMV) DNA load was determined in polymorphonuclear leukocytes (PMNL) and plasma samples from 106 human immunodeficiency virus-infected subjects at risk of developing CMV disease (group 1) and from 27 AIDS patients with documented CMV disease (group 2). For both groups, the number of CMV copies in PMNL was significantly higher than in plasma when results were derived from an equivalent blood volume (P < .001, PMNL vs. plasma). Additionally, group 2 (symptomatic) patients had a greater viral DNA load than group 1 (asymptomatic) subjects (P < .001 for both PMNL and plasma). The sensitivity, specificity, and positive and negative predictive values of qualitative polymerase chain reaction using PMNL (PCR-PMNL) for the presence of CMV disease were 100%, 58%, 38%, and 100%, respectively, compared with 70%, 93%, 74%, and 92% for qualitative PCR-plasma and 93%, 92%, 76%, and 98% for quantitative PCR-PMNL using a cutoff of 16,000 copies/mL. Thus, the best strategy for diagnosing CMV disease in these individuals relies on quantitative assessment of the viral DNA load in PMNL.

Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and hepatitis C coinfection using a noninvasive marker

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection.

Clindamycin with Primaquine vs. Trimethoprim-Sulfamethoxazole Therapy for Mild and Moderately Severe Pneumocystis carinii Pneumonia in Patients with AIDS: A Multicenter, Double-Blind, Randomized Trial (CTN 004)

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of > or = 60 kg or 240 mg/1,200 mg q.i.d. if weight of < 60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of > 70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 of < or = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

Emergence and prevalence of cytomegalovirus UL97 mutations associated with ganciclovir resistance in AIDS patients

Objectives: To evaluate the prevalence of the most common cytomegalovirus (CMV) UL97 mutations associated with ganciclovir resistance directly in polymorphonuclear leukocytes (PMNL) of patients with AIDS and CMV retinitis. Also to correlate the presence (or absence) of these mutations with the systemic CMV viral load and the ophthalmologic outcome of these subjects. Methods: Monthly blood samples were obtained from 19 patients with AIDS and CMV retinitis who had been treated with systemic ganciclovir for ≥ 2 months. Detection of CMV UL97 mutations was done using nested PCR amplification followed by restriction enzyme analysis. The viral load was assessed with a polymerase chain reaction-based assay and non-isotopic hybridization detection. Results: CMV UL97 mutations were detected in PMNL of four of 13 (30.8%) patients who had been treated with ganciclovir for ≥ 3 months but in none of six patients who had been treated for < 3 months. All four patients with detectable UL97 mutations were presenting evidence of retinitis progression at the time those mutations were first detected (mean, 145.7 days of ganciclovir) and three of four patients had a viral DNA load > 10 000 copies per 105 PMNL contrasting with the copy numbers in the 15 subjects without mutations (mean, 492.9 copies per 105 PMNL after a mean of 146.8 days of ganciclovir). Conclusions: The prevalence of the most common CMV UL97 mutations associated with ganciclovir resistance in PMNL of patients with AIDS treated for ≥ 3 months (30.8%) appears to be higher than the rate of emergence of ganciclovir-resistant CMV isolates as previously reported using phenotypic assays (about 8%). Moreover, the detection of these mutations is associated with a considerable increase in the CMV DNA load in the blood as well as with progression of CMV retinitis during ganciclovir therapy.

HIV-associated Lipodystrophy Syndrome: A Review of Clinical Aspects

Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.

A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis.

Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.

Impact of HIV-1 viral subtype on CD4+ T-cell decline and clinical outcomes in antiretroviral naive patients receiving universal healthcare.

Objective:The influence of viral subtype on the natural history of HIV is unclear and confounded by socioeconomic and host factors that vary between groups harboring different clades. We compared Canadians (clade B), with recent immigrants from Haiti (clade B) and sub-Saharan Africa (clades non-B) to determine whether there were differences in disease progression attributable to viral subtype. Methods:We conducted a retrospective cohort study in a universal healthcare setting between 1996 and 2007. The rate of CD4+ T-lymphocyte decline prior to initiation of antiretroviral therapy was determined in all participants with at least two CD4+ T-lymphocyte measures using mixed linear regression models. Time to first AIDS-defining illness was compared using adjusted Cox proportional hazards models. Results:Two hundred and eighty-nine Canadians, 44 Haitians, and 123 Africans were studied for a median of 260 days (2 days–11 years). Africans and Haitians were demographically and clinically similar. However, the adjusted slope of square root CD4+ T-lymphocyte decline was significantly lower in Africans [−0.04/year; 95% confidence interval (CI) = −0.08 to −0.003] compared with Canadians (−0.07/year; 95% CI = −0.11 to −0.03; P = 0.02), and Haitians (−0.10/year; 95% CI = −0.12 to −0.07; P = 0.001). Africans were also less likely to develop AIDS. Conclusion:Despite having similar demographic, socioeconomic, and nutritional status to Haitians, Africans infected with non-B clade HIV had slower rates of disease progression compared with both Haitians and Canadians, with both groups being infected by the clade B virus. Our findings suggest that viral subtype may be an important predictor of HIV natural history in a developed medical setting.