Carlos Brites

Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.

BACKGROUND Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. METHODS ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. FINDINGS Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). INTERPRETATION Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. FUNDING ViiV Healthcare.

Ultrasensitive Monitoring of HIV-1 Viral Load by a Low-Cost Real-Time Reverse Transcription-PCR Assay with Internal Control for the 5′ Long Terminal Repeat Domain

Abstract Background: Current HIV-1 viral-load assays are too expensive for resource-limited settings. In some countries, monitoring of antiretroviral therapy is now more expensive than treatment itself. In addition, some commercial assays have shown shortcomings in quantifying rare genotypes. Methods: We evaluated real-time reverse transcription-PCR with internal control targeting the conserved long terminal repeat (LTR) domain of HIV-1 on reference panels and patient samples from Brazil (n = 1186), South Africa (n = 130), India (n = 44), and Germany (n = 127). Results: The detection limit was 31.9 IU of HIV-1 RNA/mL of plasma (>95% probability of detection, Probit analysis). The internal control showed inhibition in 3.7% of samples (95% confidence interval, 2.32%–5.9%; n = 454; 40 different runs). Comparative qualitative testing yielded the following: Roche Amplicor vs LTR assay (n = 431 samples), 51.7% vs 65% positives; Amplicor Ultrasensitive vs LTR (n = 133), 81.2% vs 82.7%; BioMerieux NucliSens HIV-1 QT (n = 453), 60.5% vs 65.1%; Bayer Versant 3.0 (n = 433), 57.7% vs 55.4%; total (n = 1450), 59.0% vs 63.8% positives. Intra-/interassay variability at medium and near-negative concentrations was 18%–51%. The quantification range was 50–10 000 000 IU/mL. Viral loads for subtypes A–D, F–J, AE, and AG yielded mean differences of 0.31 log10 compared with Amplicor in the 103–104 IU/mL range. HIV-1 N and O were not detected by Amplicor, but yielded up to 180 180.00 IU/mL in the LTR assay. Viral loads in stored samples from all countries, compared with Amplicor, NucliSens, or Versant, yielded regression line slopes (SD) of 0.9 (0.13) (P <0.001 for all). Conclusions: This method offers all features of commercial assays and covers all relevant genotypes. It could allow general monitoring of antiretroviral therapy in resource-limited settings.

High prevalence of giardiasis and strongyloidiasis among HIV-infected patients in Bahia, Brazil

Diarrhea due to intestinal microbial infections is a frequent manifestation among HIV-infected patients. It has been postulated that HIV-infected patients may have special types of intestinal infections, and that immune activation from such parasites may affect the progression of HIV disease. To evaluate these associations, the frequency of infections was examined in HIV-infected patients in Bahia, Brazil. To determine the potential impact of the presence of intestinal parasitic infections on HIV disease progression, a retrospective study approach was used. The medical charts of 365 HIV-infected patients who had been treated at the AIDS Clinic of the Federal University of Bahia Hospital were reviewed, and the prevalence of parasites was compared with 5,243 HIV-negative patients who had attended the hospital during the same period of time. Among HIV-infected subjects, CD(4) count, RNA plasma viral load (VL), and number of eosinophils were compared according to their stool examination results. The overall prevalence of each parasite was similar for HIV-positive and HIV-negative patients. However, the prevalence of S. stercoralis (p<10(-7)) and G. lamblia (p=0.005) was greater for HIV-infected subjects. The mean CD(4) count and viral load of HIV patients in our clinic who had stool examinations was 350 cells +/- 340 and 4.4 +/- 1.4 log RNA viral load, respectively. In this patient group there was no clear association between the level of the absolute CD(4) count or the viral load and a specific parasitic infection. The presence of an intestinal parasitic infection was not associated with faster progression of the HIV disease among HIV-infected patients. We conclude that strongyloidiasis and giardiasis are more frequent in HIV-infected patients in Bahia, Brazil. If this association is due to immune dysregulation, as has been proposed elsewhere, it must occur in patients after only minor shifts in CD(4) count from normal levels, or as a result of immune dysfunction not represented by CD(4) count. These infections do not appear to alter the progression of HIV disease.

Severe and Norwegian scabies are strongly associated with retroviral (HIV-1/HTLV-1) infection in Bahia, Brazil.

Severe scabies has been associated with HTLV infection. To evaluate the impact of HTLV-I/HIV-1 co-infection on the clinical presentation of scabies, we reviewed 91 cases of scabies in Bahia, Brazil, during a 3 year period. Infections by HIV-1 (50%), HTLV-I (32%), and both (20%) were highly prevalent. Crusted or severe scabies were strongly associated with HTLV-I and, to a lesser degree, with HIV-1 infection. Co-infected patients had a higher risk of death (P = 0.01). Severe forms of scabies were highly predictive of double retroviral infection.

Adult T-cell leukemia/lymphoma in Bahia, Brazil: analysis of prognostic factors in a group of 70 patients.

The purpose of this study was to evaluate whether subdivision of adult T-cell leukemia/lymphoma (ATL) on the basis of clinical types, skin involvement, histologic features, cell size, and proliferative index (PI) was clinically relevant. Skin lesions were present in 47 cases (67%). Five cases were classified as primary cutaneous tumoral (PCT) type not included in the Shimoyama classification and characterized by skin tumors and absence of systemic involvement, lymphocytosis, and hypercalcemia. Mortality was high (61/70 [87%]). The overall median survival time (MST) was 12 months. The following variables were adversely related to survival: acute, lymphoma, and PCT types; absence of skin lesions; large cells; and PI more than 18%. The longer MST observed in cases with skin lesions was probably due to prolonged survival of the smoldering type (58 months). The MST of the PCT type (21 months) was shorter than that of the smoldering type, confirming the importance of clearly defining these 2 types of ATL.

Infective Dermatitis and Human T Cell Lymphotropic Virus Type 1–Associated Myelopathy/Tropical Spastic Paraparesis in Childhood and Adolescence

BACKGROUND Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (IDH) is a chronic and recurrent eczema occurring during childhood and adolescence. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy of adulthood, presenting with slowly progressive spastic paraparesis and sphincter dysfunction with mild sensory involvement. There are few reports describing an association between IDH and HAM/TSP. The objective of this study was to evaluate the occurrence of HAM/TSP in patients with IDH and in seropositive members of their families and to determine the blood levels of antibodies against HTLV-1 in patients with HAM/TSP. METHODS Twenty patients with IDH and their seropositive mothers and siblings underwent clinical, neurological, and laboratory evaluations. The diagnosis of HAM/TSP was made in accordance with the World Health Organization criteria. RESULTS Nine individuals had HAM/TSP (6 of the patients with IDH, 2 mothers, and 1 seropositive brother). In 3 families, > 1 individual had HAM/TSP. The serum antibody titers of the patients with HAM/TSP varied from 1 : 3.125 to 1 : 78.125. CONCLUSIONS A strong association was observed between IDH and HAM/TSP. The familial clustering of both diseases suggests a genetic background. Serological screening for HTLV-1 in children with symptoms of myelopathy is essential in areas where HTLV-1 is endemic.

Infective Dermatitis Associated with the Human T Cell Lymphotropic Virus Type I in Salvador, Bahia, Brazil

BACKGROUND Infective dermatitis associated with human T cell lymphotropic virus type I (HTLV-I) infection is a chronic, relapsing eczema of childhood. METHODS Children, their mothers, and their siblings underwent serological testing for HTLV-I. Epidemiological data were collected from all seropositive children and their family members, and clinical and dermatological examinations were performed. Laboratory studies, including skin culture, and histopathological analyses were also performed. The diagnosis of infective dermatitis associated with HTLV-I (IDH) was made according to previously established criteria. RESULTS All of the patients with cases that demonstrated clinical aspects of IDH were positive for HTLV-I. The median age of the children at the time of the first visit was 8.0 years (range, 2-14 years). The median duration of breastfeeding for 19 children was 22.5 months (range, 1-48 months). The lesions were erythematous, scaly, exudative, and crusted in all cases. The scalp, retroauricular areas, neck, and groin were the regions that were commonly affected. Cultures were positive for Staphylococcus aureus for 95% of the patients. The children were followed-up for a median of 3.0 years (range, 0.1-7 years), and 5 children developed HTLV-I-associated myelopathy/tropical spastic paraparesis. All of the children except 1 were treated with sulfamethoxazole-trimethoprim, and their lesions either improved greatly or completely disappeared. CONCLUSIONS The present study demonstrates the severity of IDH in Bahia and confirms that its diagnosis is based almost exclusively on clinical aspects of the disease. Serological testing for HTLV-I and careful follow-up is recommended for all children with chronic, relapsing, severe eczema in regions where HTLV-I is endemic.

Efficacy and safety of Efavirenz in HIV patients on Rifampin for tuberculosis

Forty-nine AIDS patients, most of who were antiretroviral therapy (ARV) naive, with active tuberculosis, were treated with Rifampin 600 mg, Isoniazid 400 mg and Pirazinamide 2 g daily. They also received ARV, consisting of Efavirenz (600 mg/day) plus 2 NRTIs. All patients were prospectively followed for at least 24 months. Baselines were: male/female ratio 2:1, mean age 34.7 +/- 9.4 yrs; weight 51 +/- 9.0 kg, viral load 5.6 +/- 0.6 logs, CD4 cell count 101 +/- 128 cells/ mm3. Follow up mean values of data logs of VL and CD4+ cell /mm3 counts were: VL 1.7 and CD4+ 265; VL 1.3 and CD4+ 251; VL 1.4 and CD4+ 326 at 6, 12 and 24 months, respectively. Weight gain changes were: 5 +/- 9.9 +/- 12 and 21 +/- 16 kg respectively at 6, 12 and 24 months. A non-concomitant ARV regimen was introduced at least three weeks after TB treatment initiation. Severe adverse reactions included rash (two), toxic hepatitis (six), Immune Reconstitution Syndrome (seven), and four deaths. We conclude that Efavirenz at a daily dose of 600 mg is sufficient and safe to treat HIV/TB patients using a Rifampin containing regimen.

Evaluation of blood stream infections by Candida in three tertiary hospitals in Salvador, Brazil: a case-control study

Invasive infections caused by Candida spp. are an important problem in immunocompromised patients. There is scarce data on the epidemiology of blood stream candidiasis in Salvador, Brazil. This study evaluates the risk factors associated with candidemia, among patients admitted to three tertiary, private hospitals, in Salvador, Brazil. We conducted a case-control, retrospective study to compare patients with diagnosis of candidemia in three different tertiary hospitals in Salvador, Brazil. Patients were matched for nosocomial, acquired infections, according to the causal agent: cases were defined by positive blood cultures for Candida species. Controls were those patients who had a diagnosis of systemic bacterial infection, with a positive blood culture to any bacteria, within the same time period (+/- 30 days) of case identification. The groups were compared for the main known risk factors for candidemia and for mortality rates. A hundred thirty-eight patients were identified. Among the 69 cases, only 14 were diagnosed as infected by Candida albicans. Candida species were defined in only eight cultures: C. tropicalis (4 cases), C. glabrata, C. parapsilosis, C. guillermondi, C. formata (1 case each). The main risk factors, identified in a univariate analysis, were: presence of a central venous catheter (CVC), use of parenteral nutrition support (PNS), previous exposure to antibiotics, and chronic renal failure (CRF). No association was detected with surgical procedures, diabetes mellitus, neutropenia or malignancies. Patients were more likely to die during the hospitalization period, but the rates of death caused by the infections were similar for cases and controls. The length of hospitalization was similar for both groups, as well as the time for a positive blood culture. Blood stream infection by Candida spp. is associated with CVC, PNS, previous use of antibiotics, and CRF. The higher mortality rate for cases probably better reflects the severity of the underlying diseases, than as a direct consequence of Candidemia.

Co-infection with HTLV-1 is associated with a shorter survival time for HIV-1-infected patients in Bahia, Brazil

Co-infection with HTLV-1 reaches 20% among patients infected by HIV-1 in Bahia, Brazil. To evaluate its impact on survival, we conducted a retrospective, case-control study involving 198 patients (63 cases). Co-infection was associated with parenteral exposure (P = 0.0001) and female sex (P = 0.02). Co-infected patients had a shorter mean survival (1849 days) than controls (2430 days, P = 0.001), regardless of sex or baseline CD4 cell count. In Bahia, Brazil, co-infection with HIV-1 and HTLV-1 is associated with a shorter survival time.