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1.  HIV-associated lipodystrophy: a review from a Brazilian perspective 
The prognosis of human immunodeficiency virus (HIV)-infected individuals has dramatically improved worldwide since the introduction of highly antiretroviral therapy. Nevertheless, along with the decrease in mortality, several body modifications not initially related to HIV infection have been reported. Disorders in lipid and glucose metabolism, accompanied by body shape abnormalities and alterations in fat distribution, began to be described. A syndrome, named “HIV-associated lipodystrophy syndrome”, was coined to classify these clinical spectrum aspects. This syndrome involves not only metabolic alterations but also fat redistribution, with lipoatrophy due to subcutaneous fat loss (predominantly in the face and lower limbs) and lipohypertrophy related to central fat gain. These changes in body shape are very important to be recognized, as they are associated with worse morbidity and mortality. Self-esteem difficulties related to body alterations might lead to treatment failures due to medication adherence problems. Moreover, these alterations have been associated with an increased risk of cardiovascular events. Therefore, it is extremely important to identify this syndrome early in order to provide an even better quality of life for this population, as the clinical approach is not easy. Treatment change, medications to treat dyslipidemia, and surgical intervention are instruments to be used to try to correct these abnormalities. The aim of this study is to review clinical presentation, diagnosis, and management of body shape and metabolic complications of HIV infection from a Brazilian perspective, a medium income country with a large number of patients on antiretroviral therapy.
PMCID: PMC4108257  PMID: 25083134
lipoatrophy; lipodystrophy; lipohypertrophy; HAART; dyslipidemia; Brazil
2.  Genetic Markers Associated to Dyslipidemia in HIV-Infected Individuals on HAART 
The Scientific World Journal  2013;2013:608415.
This study evaluated the impact of 9 single nucleotide polymorphisms (SNPs) in 6 candidate genes (APOB, APOA5, APOE, APOC3, SCAP, and LDLR) over dyslipidemia in HIV-infected patients on stable antiretroviral therapy (ART) with undetectable viral loads. Blood samples were collected from 614 patients at reference services in the cities of Porto Alegre, Pelotas, and Rio Grande in Brazil. The SNPs were genotyped by conventional polymerase chain reaction (PCR) and real-time PCR. The prevalence of dyslipidemia was particularly high among the protease inhibitors-treated patients (79%). APOE (rs429358 and rs7412) genotypes and APOA5 −1131T>C (rs662799) were associated with plasma triglycerides (TG) and low-density-lipoprotein cholesterol levels (LDL-C). The APOA5 −1131T>C (rs662799) and SCAP 2386A>G (rs12487736) polymorphisms were significantly associated with high-density-lipoprotein cholesterol levels. The mean values of the total cholesterol and LDL-C levels were associated with both the APOB SP Ins/Del (rs17240441) and APOB XbaI (rs693) polymorphisms. In conclusion, our data support the importance of genetic factors in the determination of lipid levels in HIV-infected individuals. Due to the relatively high number of carriers of these risk variants, studies to verify treatment implications of genotyping before HAART initiation may be advisable to guide the selection of an appropriate antiretroviral therapy regimen.
PMCID: PMC3804371  PMID: 24191141
3.  Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy 
To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment.
Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/μl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements ≥10 0000 copies/ml (higher threshold) or ≥500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated.
A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6–33.6%) for the higher and 12.6% (6.7–21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3–97.8%) and 97.3% (96.5–98.0%), for positive predictive value 9.5% (3.6–19.6%) and 19.0% (10.2–30.9%) and for negative predictive value 98.5% (97.9–99.0%) and 95.7% (94.7–96.6%).
The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.
PMCID: PMC3722497  PMID: 19624478
highly active antiretroviral therapy; treatment failure; CD4 lymphocyte count; viral load; diagnostic techniques and procedures; Africa
4.  Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings 
BMC Infectious Diseases  2012;12:147.
Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART.
Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART.
3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12.
In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.
PMCID: PMC3573925  PMID: 22742573
HIV-1; CD4 count; CD4 slope; HIV-RNA threshold; Resource limited settings
5.  Tuberculosis in HIV Programmes in Lower-Income Countries: Practices and Risk Factors 
Tuberculosis (TB) is a common diagnosis in HIV-infected patients on antiretroviral therapy (ART).
To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART.
Programme characteristics were assessed by standardized electronic questionnaire. Patient data from 2003-2008 were analyzed and incidence rate ratios (IRRs) calculated using Poisson regression models.
Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes, respectively. Eight sites (53.3%) used directly observed therapy and five (33.3%) routinely administered isoniazid preventive therapy (IPT). A total of 19,413 patients aged ≥16 years contributed 13,227 person-years of follow-up; 1,081 new TB events were diagnosed. Risk factors included CD4 cell count (adjusted IRR comparing >350 cells/μL with <25 cells/μL 0.46, 95% CI 0.33-0.64, P<0.0001), gender (adjusted IRR comparing women with men 0.77, 0.68-0.88, P=0.0001) and use of IPT (IRR 0.24, 95% CI 0.19-0.31, p<0.0001).
Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.
PMCID: PMC3140103  PMID: 21756512
tuberculosis; HIV; prevention; access; diagnostics; treatment practices; antiretroviral therapy; lower income countries; immunodeficiency; risk factor
6.  Prevalence and Risk Factors Associated to Chronic Kidney Disease in HIV-Infected Patients on HAART and Undetectable Viral Load in Brazil 
PLoS ONE  2011;6(10):e26042.
To determine the prevalence and associated factors with chronic kidney disease (CKD) in a cohort of HIV-positive individuals with undetectable viral load on HAART.
From March, 2009 to September 2009, 213 individuals between 18-70 years, period on HAART ≥12 months, viral load < 50 copies/mm3, and CD4 ≥ 200 cells/mm3, were consecutively enrolled at the outpatient clinic of Hospital de Clínicas, Porto Alegre, Brazil. Exclusion criteria were obesity, malnourishment, amputee, paraplegic, previous history of renal disease, pregnancy and hepatic insufficiency. Renal function was determined by estimated glomerular filtration rate (eGFR) assessed by the modification of diet in renal disease. CKD was defined as an eGFR less or equal than 60 ml/min/1.73 m2, for a period of at least 3 months. Poisson regression was used to determine factors associated with CKD.
CKD was diagnosed in 8.4% of the population, and after adjustment, the risk factors were hypertension (RR = 3.88, 95%CI, 1.84 - 8.16), time on HAART (RR = 1.15, 95%CI,1.03–1.27) and tenofovir exposure (RR = 2.25, 95%CI, 1.04–4.95). Higher weight (RR = ,0.88 95%CI, 0.82–0.96) was associated to normal function.
CKD was a common finding in this cohort of patients and was related to hypertension, time on HAART and tenofovir exposure. We suggest a more frequent monitoring of renal function, especially for those with risk factors to early identify renal impairment.
PMCID: PMC3192150  PMID: 22022501
7.  Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring 
AIDS (London, England)  2009;23(14):1867-1874.
In high-income countries viral load (VL) is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. VL monitoring is not generally available in resource-limited settings. We examined switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor (PI)-based regimens in Africa, South America and Asia.
Design and methods
Multi-cohort study of 17 ART programmes. All sites monitored CD4 counts and had access to second-line ART, 10 sites monitored VL. We compared times to switching, CD4 counts at switching and obtained adjusted hazard ratios for switching (aHR) with 95% confidence intervals (CIs) from random-effects Weibull models.
A total of 20,113 patients, including 6,369 (31.7%) patients from 10 programmes with access to VL monitoring were analysed; 576 patients (2.9%) switched. Low CD4 counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months (interquartile range [IQR] 10.1–26.6) in programmes with VL and 21.8 months (IQR 14.0–21.8) in programmes without VL monitoring (p<0.001). Median CD4 cell counts at switching were 161 cells/μl (IQR 77–265) and 102 cells/μl (44–181), respectively (p<0.001). Switching was more common in programmes with VL monitoring during months 7–18 after starting ART (aHR 1.38; 95% CI 0.97–1.98), similar during months 19–30 (aHR 0.97; 0.58–1.60) and less common during months 31–42 (aHR 0.29; 0.11–0.79).
In resource-limited settings switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with VL monitoring compared to programmes without VL monitoring.
PMCID: PMC2956749  PMID: 19531928
Adolescent; Adult; Anti-HIV Agents; therapeutic use; Antiretroviral Therapy, Highly Active; adverse effects; methods; CD4 Lymphocyte Count; Developing Countries; Drug Monitoring; methods; Female; HIV Infections; drug therapy; immunology; virology; HIV Protease Inhibitors; therapeutic use; HIV-1; isolation & purification; Humans; Male; Medically Underserved Area; Middle Aged; Reverse Transcriptase Inhibitors; therapeutic use; Time Factors; Treatment Failure; Viral Load; Young Adult; Antiretroviral therapy; switching to second-line regimens; resource-limited settings; CD4 cell count; viral load monitoring; cohort studies; collaborative research
8.  Long-term immunologic response to antiretroviral therapy in low-income countries: Collaborative analysis of prospective studies 
AIDS (London, England)  2008;22(17):2291-2302.
Few data are available on the long-term immunologic response to ART in resource-limited settings, where antiretroviral therapy (ART) is being scaled up using a public health approach, with a limited repertoire of drugs.
To describe immunologic response to ART in a network of cohorts from sub-Saharan Africa, Latin America, and Asia.
Study population/methods
Treatment-naïve patients aged 15 and older from 27 treatment programs were eligible. Multi-level, linear mixed models were used to assess associations between predictor variables and CD4 count trajectories following ART initiation.
Of 29,175 patients initiating ART, 8,933 patients (31%) were excluded due to insufficient follow-up time and early lost to follow-up or death. The remaining 19,967 patients contributed 39,200 person-years on ART and 71,067 CD4 measurements. The median baseline CD4 count was 114 cells/μL, with 35%<100 cells μL and substantial inter-site variation (range: 61-181 cells/μL). Females had higher median baseline CD4 counts than males (121 vs. 104 cells/μL). The median CD4 count increased from 114 cells/μL at ART initiation to 230 (IQR:144-338) at 6 months, 263 (IQR:175-376) at 1 year, 336 (IQR:224-472) at 2 years, 372 (IQR:242-537) at 3 years, 377 (IQR:221-561) at 4 years, and 395 (IQR:240-592) at 5 years. In multivariable models, baseline CD4 count was the most important determinant of subsequent CD4 count trajectories.
These data demonstrate robust and sustained CD4 response to ART among patients remaining on therapy. Public health and programmatic interventions leading to earlier HIV diagnosis and initiation of ART could substantially improve patient outcomes in resource-limited settings.
PMCID: PMC2794130  PMID: 18981768
antiretroviral therapy; CD4 response; CD4 lymphocyte count; low-income countries; baseline CD4 count; ART-LINC; IeDEA
9.  Conservation Patterns of HIV-1 RT Connection and RNase H Domains: Identification of New Mutations in NRTI-Treated Patients 
PLoS ONE  2008;3(3):e1781.
Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood.
Methods and Findings
We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naïve and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher's exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI.
This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions.
PMCID: PMC2262134  PMID: 18335052
10.  Differential Drug Resistance Acquisition in HIV-1 of Subtypes B and C 
PLoS ONE  2007;2(8):e730.
Subtype C is the most prevalent HIV-1 subtype in the world, mainly in countries with the highest HIV prevalence. However, few studies have evaluated the impact of antiretroviral therapy on this subtype. In southern Brazil, the first developing country to offer free and universal treatment, subtypes B and C co-circulate with equal prevalence, allowing for an extensive evaluation of this issue.
Methods and Findings
Viral RNA of 160 HIV-1+ patients was extracted, and the protease and reverse transcriptase genes were sequenced, subtyped and analyzed for ARV mutations. Sequences were grouped by subtype, and matched to type (PI, NRTI and NNRTI) and time of ARV exposure. Statistical analyses were performed to compare differences in the frequency of ARV-associated mutations. There were no significant differences in time of treatment between subtypes B and C groups, although they showed distinct proportions of resistant strains at different intervals for two of three ARV classes. For PI, 26% of subtype B strains were resistant, compared to only 8% in subtype C (p = 0.0288, Fisher's exact test). For NRTI, 54% of subtype B strains were resistant versus 23% of subtype C (p = 0.0012). Differences were significant from 4 years of exposure, and remained so until the last time point analyzed. The differences observed between both subtypes were independent of time under rebound viremia in cases of virologic failure and of the number of HAART regimens used by treated patients.
Our results pointed out to a lower rate of accumulation of mutations conferring resistance to ARV in subtype C than in subtype B. These findings are of crucial importance for current initiatives of ARV therapy roll-out in developing countries, where subtype is C prevalent.
PMCID: PMC1939879  PMID: 17710130

Results 1-10 (10)