Nathan Clumeck

Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

BACKGROUND CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

BACKGROUND It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

Isolation of aids virus from cell-free breast milk of three healthy virus carriers

The authors investigated postnatal transmission of acquired immunodeficiency syndrome (AIDS) to 3 breastfed infants whose mothers had been virus free at birth but became infected shortly afterward as a result of blood transfusions. In the 1st family the 5-month old infant was admitted to the hospital with splenomegaly fever failure to thrive and nonoathogenic diarrhea. She had not been given any blood products and was breastfed. The father was from Belgium and the mother from Zaire. In the 2nd family the father who had lived in Zaire for 10 years had generalized lymphadenopathy presumably a result of a blood transfusion. In the 3rd family the infant had a maculopapular rash at 2 months and began to show failure to thrive and fever. At 5 months she developed interstitial pneumonia. Both parents were from Rwanda. Breast milk samples provoked the appearance to human T-lymphotropic virus type III (HTLV-III) antigens. 2 mothers had antibodies to HTLV-III in their serum and antibodies in milk should now be investigated.

ACQUIRED IMMUNODEFICIENCY SYNDROME IN RWANDA

To evaluate acquired immunodeficiency syndrome (AIDS) in central Africa a prospective study was done in Kigali, Rwanda, where Kaposis sarcoma (KS) is endemic. During a 4 week period, 26 patients (17 males and 9 females) were diagnosed. 16 patients had opportunistic infections, associated with KS in only 2; 1 had multifocal KS alone; and 9 had clinical conditions consistent with prodromes of AIDS. All patients had severe T-cell defects characterised by cutaneous anergy, a striking decrease in the number of helper T cells, and a decreased OKT4:OKT8 ratio (mean 0.27). 21 of the 22 adult patients were living in urban centres and many of them were in the middle to upper income bracket. Most of the men were promiscuous heterosexuals and 43% of the females were prostitutes. No patient had a history of homosexuality, intravenous drug abuse, or transfusion in the previous 5 years. This study suggests that AIDS is present in central Africa as an entity probably unrelated to the well-known endemic African KS. An association of an urban environment, a relatively high income, and heterosexual promiscuity could be a risk factor for AIDS in Africa.

Maraviroc versus Efavirenz, Both in Combination with Zidovudine-Lamivudine, for the Treatment of Antiretroviral-Naive Subjects with CCR5-tropic HIV-1 Infection

BACKGROUND The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. METHODS Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. RESULTS The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point. CONCLUSIONS Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

Treatment of Toxoplasmic Encephalitis in Patients with AIDS: A Randomized Trial Comparing Pyrimethamine plus Clindamycin to Pyrimethamine plus Sulfadiazine

OBJECTIVE To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. SETTING University hospitals. PATIENTS Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. INTERVENTIONS Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. MEASUREMENTS AND MAIN RESULTS There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. CONCLUSIONS The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults

A working group of the European AIDS Clinical Society (EACS) have developed these guidelines for European clinicians to help them in the treatment of adults with HIV infection. This third version of the guidelines includes, as new topics, the assessment of patients at initial and subsequent clinic visits as well as post‐exposure prophylaxis. A revision of the 2005 guidelines based on current data includes changes in the sections on primary HIV infection, when to initiate therapy, which drug combinations are preferred as initial combination regimens for antiretroviral‐naïve patients, how to manage virological failure and the treatment of HIV during pregnancy.

Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

BACKGROUND Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter

BACKGROUND Zidovudine therapy is of benefit in the treatment of symptomatic and asymptomatic human immunodeficiency virus (HIV) infection in persons with CD4+ cell counts of less than 500 per cubic millimeter. The efficacy, safety, and duration of benefit of zidovudine in those with 500 or more CD4+ cells per cubic millimeter are uncertain. METHODS In a double-blind, placebo-controlled trial, 993 patients with asymptomatic HIV infection and CD4+ cell counts above 400 per cubic millimeter were randomly assigned to receive zidovudine (500 mg twice daily) or placebo for three years. The primary end point was progression of disease, as defined by the development of Centers for Disease Control and Prevention (CDC) group IV disease (including recurrent oral candidiasis, hairy leukoplakia, or progressive diarrhea) or two CD4+ cell counts below 350 per cubic millimeter. This outcome measure was changed from the original end point of the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex to reflect changes in recommendations for management. The study was terminated after the first interim analysis. RESULTS Disease progression was significantly less frequent in the zidovudine group (relative risk, 0.56; 95 percent confidence interval, 0.43 to 0.75; P < 0.001 by the log-rank test). The probability of disease progression at two years was 0.19 with zidovudine, as compared with 0.34 with placebo (95 percent confidence interval for the difference, -0.21 to -0.08). Progression to CDC group IV disease was reduced by half in the zidovudine recipients (relative risk, 0.49; P = 0.049) and decline in CD4+ cell counts to below 350 per cubic millimeter was reduced by 40 percent (relative risk, 0.60; P < 0.001). The inclusion of early HIV disease events (oral candidiasis, oral hairy leukoplakia, and herpes zoster) as end points confirmed the effects of zidovudine on the progression of clinical disease (relative risk, 0.55; 95 percent confidence interval, 0.37 to 0.84; P = 0.004). The median duration of treatment was 94 weeks. Severe hematologic or clinical side effects were rare. CONCLUSIONS Treatment with zidovudine benefits HIV-infected persons with CD4+ cell counts above 400 per cubic millimeter. Despite the use of doses larger than those now generally prescribed, zidovudine was well tolerated for up to three years by most of our patients.

Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study

BACKGROUND Combination antiretroviral therapy (cART) has been shown to reduce mortality and morbidity in patients with HIV. As viral replication falls, the CD4 count increases, but whether the CD4 count returns to the level seen in HIV-negative people is unknown. We aimed to assess whether the CD4 count for patients with maximum virological suppression (viral load <50 copies per mL) continues to increase with long-term cART to reach levels seen in HIV-negative populations. METHODS We compared increases in CD4 counts in 1835 antiretroviral-naive patients who started cART from EuroSIDA, a pan-European observational cohort study. Rate of increase in CD4 count (per year) occurring between pairs of consecutive viral loads below 50 copies per mL was estimated using generalised linear models, accounting for multiple measurements for individual patients. FINDINGS The median CD4 count at starting cART was 204 cells per microL (IQR 85-330). The greatest mean yearly increase in CD4 count of 100 cells per microL was seen in the year after starting cART. Significant, but lower, yearly increases in CD4 count, around 50 cells per microL, were seen even at 5 years after starting cART in patients whose current CD4 count was less than 500 cells per microL. The only groups without significant increases in CD4 count were those where cART had been taken for more than 5 years with a current CD4 count of more than 500 cells per microL, (current mean CD4 count 774 cells per microL; 95% CI 764-783). Patients starting cART with low CD4 counts (<200 cells per microL) had significant rises in CD4 counts even after 5 years of cART. INTERPRETATION Normalisation of CD4 counts in HIV-infected patients for all infected individuals might be achievable if viral suppression with cART can be maintained for a sufficiently long period of time.