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1.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
2.  Renal disease in HIV infected Individuals 
Current Opinion in HIV and AIDS  2011;6(4):285-289.
Purpose of Review
Highly Active Antiretroviral Therapy (HAART) has resulted in a marked decrease in AIDS-related conditions and death. With improved survival, cardiovascular disease (CVD), hepatic, renal disease and non-AIDS related cancers represent an increasing burden for HIV infected individuals.
Recent Findings
HIV Associated Nephropathy (HIVAN), acute renal injury, HAART, and co-morbid conditions such as Hepatitis C, hypertension and diabetes are among the multiple causes of renal disease. In HIVAN there is incomplete understanding of the interaction of the virus with renal cellsand the host genetics leading to susceptibility to this form of renal dysfunction. There is agreement that a baseline estimate of glomerular filtration (eGFR) should be obtained and that renal function should be monitored during antiretroviral therapy. There is, however no agreement as to the most accurate method of estimating GFR. Renal transplantation has emerged as a feasible and successful modality of management of end stage renal disease (ESRD) in HIV infected individuals.
Kidney disease represents an increasing concern in the care of HIV infected persons although there are questions remaining regarding the pathophysiology of HIVAN. Transplantation, however, can be carried out safely in infected persons with ESRD.
PMCID: PMC3266688  PMID: 21519246
HIV Associated Nephropathy; Estimates of Glomerular filtration; Renal transplantation of HIV infected patients with end stage renal disease; Effects of anitiretroviral drugs upon renal function
3.  Impact of Antiretroviral Therapy on Renal Function among HIV-Infected Tanzanian Adults: A Retrospective Cohort Study 
PLoS ONE  2014;9(2):e89573.
Data regarding the outcomes of HIV-infected adults with baseline renal dysfunction who start antiretroviral therapy are conflicting.
We followed up a previously-published cohort of HIV-infected adult outpatients in northwest Tanzania who had high prevalence of renal dysfunction at the time of starting antiretroviral therapy (between November 2009 and February 2010). Patients had serum creatinine, proteinuria, microalbuminuria, and CD4+ T-cell count measured at the time of antiretroviral therapy initiation and at follow-up. We used the adjusted Cockroft-Gault equation to calculate estimated glomerular filtration rates (eGFRs).
In this cohort of 171 adults who had taken antiretroviral therapy for a median of two years, the prevalence of renal dysfunction (eGFR <90 mL/min/1.73 m2) decreased from 131/171 (76.6%) at the time of ART initiation to 50/171 (29.2%) at the time of follow-up (p<0.001). Moderate dysfunction (eGFR<60 mL/min/1.73 m2) decreased from 21.1% at antiretroviral therapy initiation to 1.1% at follow-up (p<0.001), as did the prevalence of microalbuminuria (72% to 44%, p<0.001). Use of tenofovir was not associated with renal dysfunction at follow-up.
Mild and moderate renal dysfunction were common in this cohort of HIV-infected adults initiating antiretroviral therapy, and both significantly improved after a median follow-up time of 2 years. Our work supports the renal safety of antiretroviral therapy in African adults with mild-moderate renal dysfunction, suggesting that these regimens do not lead to renal damage in the majority of patients and that they may even improve renal function in patients with mild to moderate renal dysfunction.
PMCID: PMC3935873  PMID: 24586882
4.  Factors associated with renal dysfunction within an urban HIV-infected cohort in the era of highly active antiretroviral therapy 
HIV medicine  2009;10(6):343-350.
Kidney disease remains a prevalent problem in HIV care. The contribution of highly active antiretroviral therapy (HAART), HIV disease factors and traditional factors needs further evaluation.
A cross-sectional study of all patients seen at an HIV outpatient clinic during 2005 was performed. All data were collected from medical record review. Multivariate regression modelling was used to identify independent predictors of lower glomerular filtration rate (eGFR) and chronic renal failure (CRF) from factors significant in univariate analysis. eGFR was calculated using the simplified modification of diet in renal disease equation. Results were compared with those for persons from the National Health and Nutrition Examination Survey (NHANES) matched for age, race and gender.
Of 845 HIV-infected persons, 64% were men and 34% were Caucasian, and the mean age was 39.8 years. Thirty per cent of the patients had proteinuria and 43% had eGFR<90 mL/min/1.73 m2. Persons on HAART (63%) had a lower mean eGFR than those not on HAART (92.0 vs. 101.6). In multivariate analyses, significant predictors of eGFR decline were diagnoses of hypertension, hyperlipidaemia, proteinuria, use of tenofovir or stavudine, and lower viral load. Compared with those in NHANES, HIV-infected persons had a lower mean eGFR (94.9 vs. 104.2) and a higher prevalence of CRF (8% vs. 2%).
In this cohort, the prevalence of CRF is low, but remains higher than that of the general population. Clinicians should routinely screen for early asymptomatic kidney disease to address risk factors that can be treated.
PMCID: PMC3918930  PMID: 19490182
AIDS; chronic kidney disease; highly active antiretroviral therapy; HIV
5.  HIV associated nephropathy: a treatable condition 
Sexually Transmitted Infections  2001;77(2):97-100.
Objectives: To describe current knowledge on the aetiology, pathology, diagnosis, and treatment of HIV associated nephropathy.
Methods: A Medline search was performed using the key words "HIV," "nephropathy," "renal," and "kidney." A further search was performed for each of the currently licensed antiretroviral agents linked to key words "renal" or "kidney" and also using the MeSH heading "pharmacokinetics."
Results: HIV associated nephropathy is a common complication of HIV in black African and Afro-Caribbean patients and presents with progressive renal failure and heavy proteinuria. As other causes of renal failure are likely to fall in incidence among patients successfully treated with highly active antiretroviral therapy (HAART), HIV associated nephropathy will become increasingly prominent as a cause of renal impairment in HIV infected patients. Recent evidence suggests that HIV associated nephropathy will respond to HAART with a dramatic improvement in renal function.
Conclusion: HIV associated nephropathy is a treatable condition. This condition should be actively sought in HIV infected patients if they are to receive the benefits of therapy.
Key Words: HIV; nephropathy; HAART
PMCID: PMC1744263  PMID: 11287685
6.  Prevalence and Factors Associated with Renal Dysfunction Among HIV-Infected Patients 
AIDS Patient Care and STDs  2010;24(6):353-360.
Renal dysfunction is an increasingly recognized non-AIDS–defining comorbidity among HIV-infected persons. The role of HIV-related factors in renal dysfunction remains unclear. We performed a cross-sectional study at two military clinics with open access to care to determine the impact of HIV factors, including antiretroviral therapy, on renal function. Renal dysfunction was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2. We evaluated 717 HIV patients with a median age of 41 years; 92% were male, 49% Caucasian, and 38% African American; median CD4 count was 515 cells/mm3 and 73% were receiving highly active antiretroviral therapy (HAART). Twenty-two patients (3%) had renal dysfunction. Factors associated with renal dysfunction in the multivariate logistic analyses included older age (odds ratio [OR] 2.0 per 10 year increase, p = 0.006), lower CD4 nadir (OR 0.6 per 100 cell change, p = 0.02), and duration of tenofovir use (OR 1.5 per year use, p = 0.01). Among persons initiating tenofovir (n = 241), 50% experienced a reduction in GFR (median −10.5 mL/min/1.73 m2, 95% CI, −8.9 to −13.3) within 2 years. Among tenofovir users, factors associated with a reduction in GFR included female gender (p < 0.001), African American ethnicity (p = 0.003), and lower CD4 nadir (p = 0.002). In summary, renal dysfunction was relatively uncommon among our HIV-infected patients, perhaps due to their young age, lack of comorbidities, or as a result of our definition that did not include proteinuria. Renal dysfunction was associated with duration of tenofovir use. Factors associated with renal loss among tenofovir users included female gender, African American ethnicity, and CD4 nadir <200 cells/mm3. Consideration for more frequent monitoring of kidney function among these select HIV patients may be warranted.
PMCID: PMC2933561  PMID: 20515419
7.  Renal Dysfunction among HIV-Infected Patients Starting Antiretroviral Therapy in Mwanza, Tanzania 
AIDS (London, England)  2011;25(11):1421-1425.
HIV-related renal dysfunction is associated with high mortality. Data on the prevalence of renal dysfunction among HIV-infected outpatients starting antiretroviral therapy (ART) in sub-Saharan Africa is limited. Recent recommendations to include the nephrotoxic drug tenofovir in first-line ART regimens make clarification of this issue urgent.
We screened for renal dysfunction by measuring serum creatinine, proteinuria, and microalbuminuria in HIV-positive outpatients initiating ART in Mwanza, Tanzania. We excluded patients with preexisting renal disease, hypertension, diabetes, or Hepatitis C virus co-infection. Estimated glomerular filtration rates (eGFRs) were calculated by Cockroft-Gault and Modification of Diet in Renal Disease (MDRD) equations.
Only 129 (36%) of 355 enrolled patients had normal eGFRs (Grade 0 or 1) above 90 ml/min/1.73m2. Grade 2 renal dysfunction (eGFR between 60 and 89 ml/min/1.73m2) was present in 137 patients (38.6%), and 87 patients (25%) had Grade 3 dysfunction (eGFR between 30 and 59 ml/min/1.73m2). Microalbuminuria and proteinuria were detected in 72% and 36% of patients, respectively. Factors predictive of renal dysfunction in multivariate analysis included female gender (OR 3.0, 95% confidence interval (CI) [1.8–5.1], p<0.0001), Body Mass Index (BMI) <18.5 (OR 2.3 [1.3–4.1], p=0.004), CD4+ T-cell count <200 cells/mm3 (OR 2.3 [1.1–4.8], p=0.04), and World Health Organization (WHO) clinical stage II or above (OR 1.6 [1.2–2.3], p=0.001).
Renal dysfunction was highly prevalent in this population of HIV-positive outpatients initiating first ART in Tanzania. This highlights the critical and underappreciated need to monitor renal function in HIV-positive patients in sub-Saharan Africa, particularly given the increasing use of tenofovir in first-line ART.
PMCID: PMC3631352  PMID: 21572304
renal dysfunction; HIV; antiretroviral therapy; sub-Saharan Africa
8.  Sero-prevalence of hepatitis B virus and hepatitis C virus among HIV patients in a suburban University Teaching Hospital in South-East Nigeria 
Highly active antiretroviral therapy (HAART) has improved survival of human immunodeficiency virus (HIV) patients. Concurrent morbidities from liver diseases among these patients have also been observed due to co-infection with hepatitis B and C viruses (HBV and HCV). HAART reduces liver-associated morbidities and mortalities in such patients. Unfortunately free testing of HBV and HCV are not provided alongside free HIV testing and treatment in Nigeria. We assessed the seroprevalence of HBV and HCV among HIV patients presenting for treatment in our center.
This prospective study of adult patients with HIV/AIDS assessed the seroprevalence of HBV and HCV co-infection using a 19-item questionnaire and collection of 2ml venous blood for hepatitis B surface antigens (HBsAg) and anti-HCV antibodies. All previously diagnosed HIV patients of the unit were excluded from the study.
Of the 404 patients, 69.2% were females while 30.8% were males. Married participants were 59.6%, 25.3% were single and 15% were previously married. A large proportion (69%) of patients were farmers, artisans and traders. Most had some formal education; secondary (55.3%), primary 27.3%, tertiary 13.8%. HBsAg positive participants were 9 (2.2%) while 3 (0.7%) were positive for HCV. No participant had triple infection of HIV/HBV/HCV.
Seroprevalence of HBV and HCV is low among HIV patients in Orlu. However there is a need for HBV and HCV testing of all HIV positive patients to reduce morbidities and mortalities from liver diseases.
PMCID: PMC3926757  PMID: 24570778
HIV; HBV; HCV; co-infection; seroprevalence; liver disease
9.  Hepatitis C Seropositivity and Kidney Function Decline Among Women With HIV: Data From the Women's Interagency HIV Study 
How co-infection with hepatitis C virus (HCV) impacts on the trajectory of kidney function among HIV-infected patients is unclear. This study examined the effect of HCV on kidney function over time among women infected with HIV.
Study Design
Retrospective observational cohort
Setting and Participants
Study sample included participants from the Women's Interagency HIV Study who were HIV-infected and had received HCV antibody testing and serum creatinine measurement at baseline.
HCV seropositivity
Outcomes and Measurement
Estimated glomerular filtration rate (eGFR) calculated from semi-annual serum creatinine measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD) Study equation. Linear mixed models were used to evaluate the independent effect of being HCV seropositive on eGFR over time, adjusting for demographic factors, co-morbid conditions, illicit drug use, measures of HIV disease status, use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73m2).
Of the 2,684 HIV-infected women, 952 (35%) were found to be HCV seropositive. For 180 women with CKD at baseline (eGFR <60 mL/min/1.73m2), being HCV seropositive was independently associated with a fully-adjusted net decline in eGFR of about 5% per year (95% CI: 3.2 to 7.2%), relative to women who were seronegative. In contrast, HCV was not independently associated with decline in eGFR among women without low eGFR at baseline (p<0.001 for interaction).
The MDRD Study equation has not been validated as a measure of GFR among persons with HIV or HCV. Proteinuria was not included in the study analysis. Because the study is observational, the effects of residual confounding cannot be excluded.
Among HIV-infected women with CKD, co-infection with HCV is associated with a modest, but statistically significant decline in eGFR over time. More careful monitoring of kidney function may be warranted for HIV-infected patients with CKD who are also co-infected with HCV.
PMCID: PMC2997705  PMID: 19394735
hepatitis C virus; HIV; kidney diseases; women
10.  HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy 
AIDS (London, England)  2009;23(16):2143-2149.
To identify risk factors associated with kidney function decline in a contemporary cohort of treated and untreated HIV-infected patients.
We followed individuals enrolled in the Study of the Consequences Of the Protease inhibitor Era cohort for longitudinal changes in kidney function, defined as glomerular filtration rate estimated from serum creatinine (eGFR). eGFR slope was calculated using linear mixed effects models adjusted for age, sex, race, and time-updated CD4 cell count, viral load, antiretroviral therapy (ART), and comorbid conditions.
We followed 615 patients for a mean of 3.4 (± 2.5) years. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia; CD4 cell count and viral load were not associated with eGFR loss. Among patients who initiated treatment, antiretroviral exposure was associated with a +2.8 (95% confidence interval 0.8–4.7) ml/min per 1.73 m2 per year effect on eGFR slope. Although these patients appeared to benefit from ART based on the slowing of their eGFR decline, they continued to lose kidney function at a rate of −1.9 (95% confidence interval −3.7 to −0.1) ml/min per 1.73 m2 per year. In the subgroup of individuals receiving suppressive ART with viral loads maintained below 500 copies/ml, intermittent viremic episodes (blips) were strongly associated with more rapid rates of eGFR loss [−6.7 (95% confidence interval −11.1 to −2.4) ml/min per 1.73 m2 per - year].
Although ART appears to help curb kidney function decline, patients who achieved durable viral suppression continue to manifest substantial loss of eGFR. Loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease.
PMCID: PMC2839451  PMID: 19684507
antiretroviral therapy; glomerular filtration rate; HIV; kidney diseases; viral load
11.  Rates and impact of hepatitis on human immunodeficiency virus infection in a large African cohort 
AIM: To determine the rates and impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections on response to long-term highly active antiretroviral therapy (HAART) in a large human immunodeficiency virus (HIV) population in Nigeria.
METHODS: HBV and HCV as well as HIV infections are endemic in sub Saharan Africa. This was a retrospective cohort study of 19 408 adults who were recruited between June 2004 and December 2010 in the AIDS Prevention Initiative in Nigeria in Nigeria programme at Jos University Teaching Hospital. Serological assays, including HBV surface antigen (HBsAg) and hepatitis C antibody were used to categorise hepatitis status of the patients. HBsAg was determined using enzyme immunoassay (EIA) (Monolisa HBsAg Ultra3; Bio-Rad). HCV antibody was tested using third generation EIA (DIA.PRO Diagnostic, Bioprobes srl, Milan, Italy). HIV RNA levels were measured using Roche COBAS Amplicor HIV-1 monitor test version 1.5 (Roche Diagnostics, GmbH, Mannheim, Germany) with a detection limit of 400 copies/mL. Flow cytometry was used to determine CD4+ cell count (Partec, GmbH Munster, Germany). Comparison of categorical and continuous variables were achieved using Pearson’s χ2 and Kruskal Wallis tests respectively, on MedCalc for Windows, version (MedCalc Software, Mariakerke, Belgium).
RESULTS: With an overall hepatitis screening rate of over 90% for each virus; HBV, HCV and HBV/HCV were detected in 3162 (17.8%), 1983 (11.3%) and 453 (2.5%) HIV infected adults respectively. The rate of liver disease was low, but highest among HIV mono-infected patients (29, 0.11%), followed by HBV co-infected patients (15, 0.08%). Patients with HBV co-infection and triple infection had higher log10 HIV RNA loads (HBV: 4.6 copies/mL vs HIV only: 4.5 copies/mL, P < 0.0001) and more severe immune suppression (HBV: 645, 55.4%; HBV/HCV: 97, 56.7%) prior to initiation of HAART compared to HIV mono-infected patients (1852, 48.6%) (P < 0.0001). Of 3025 patients who were 4.4 years on HAART and whose CD4 cell counts results at baseline and end of follow up were available for analyses, CD4 increase was significantly lower in those with HBV co-infection (HBV: 144 cells/mm3; HBV/HCV: 105 cells/mm3) than in those with HCV co-infection (165 cells/mm3) and HIV mono-infection (150 cells/mm3) (P = 0.0008).
CONCLUSION: High rates of HBV and HCV infections were found in this HIV cohort. CD4 recovery was significantly diminished in patients with HBV co-infection.
PMCID: PMC3602477  PMID: 23538773
Human immunodeficiency virus; Hepatitis B; Hepatitis C; Africa; Liver disease
12.  Impact of comorbidities and drug therapy on development of renal impairment in a predominantly African American and Hispanic HIV clinic population 
Renal impairment in human immunodeficiency virus (HIV)-infected patients could potentially be caused by many factors. HIV-related renal impairment risks have been little studied in African Americans and Hispanics. We investigated the impact of HIV itself, highly active antiretroviral therapy (HAART), comorbidities, and non-HIV-related drug treatment on glomerular filtration rate in a predominantly African American/Hispanic HIV-infected population who had received HAART for at least one year. This study was a retrospective electronic medical record database evaluation of renal impairment risks in a largely African American/Hispanic HIV population obtaining medical care at an HIV clinic in Dallas, Texas.
Proportional hazards models were used to investigate an association between an estimated glomerular filtration rate decrease >25% from baseline (ie, renal impairment) and demographics, antiretroviral/nonantiretroviral medications, comorbidities (hypertension, diabetes mellitus, hepatitis C virus [HCV] infection, hepatitis B virus [HBV] infection), CD4+ counts, viral load, and duration patients were monitored at the clinic (time on study).
In total, 323 patients were evaluated: 82% males; 61% African American/12% Hispanic/19% Caucasian; mean age 37.9 years (standard deviation [SD] 8.5); 6% HBV-positive; 34% HCV-positive; 29% hypertensive; 3% diabetic; 52% tenofovir-treated; mean weight 75.4 kg (SD, 15.4); mean estimated glomerular filtration 114.5 mL/min/1.73 m2 (SD, 36.7) using the Modification of Diet in Renal Disease (MDRD) calculation method; mean creatinine clearance (from which estimated glomerular filtration was extrapolated) by the Cockcroft-Gault calculation method 120.6 mL/min/1.73 m2 (SD, 41.2); mean time on study 2.7 years (SD, 1.0 year). An estimated glomerular filtration rate decrease of >25% from baseline was significantly associated with time on study (P = 0.0017; hazards ratio [HR] = 0.999) and hypertension (HR = 1.706; P = 0.0158) by the MDRD method, and with age (HR = 1.039; P = 0.0077), weight (HR = 0.987; P = 0.0023), and time on study (HR = 0.999; P = 0.0043) by extrapolation of Cockcroft-Gault creatinine clearance calculation. No specific HAART agent was associated with significant renal impairment risk by the definition used in this study.
This retrospective database study showed time on study, hypertension, weight, and age to be the only significant predictors of an estimated glomerular filtration rate decrease >25% from baseline.
PMCID: PMC3218712  PMID: 22096402
nephropathy; antiretroviral therapy; comorbidities; tenofovir; African American; Hispanic
13.  Gene-Gene and Gene-Environment Interactions in HIV-Associated Nephropathy: a Focus on the MYH9 Nephropathy Susceptibility Gene 
Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in African Americans. The HIV-1 virus infects podocytes, cells integral to formation of the glomerular filtration barrier, often leading to focal segmental glomerulosclerosis. HIVAN is typically a complication of late-stage HIV infection, associated with low CD4 cell counts and elevated serum HIV RNA levels. Highly active antiretroviral therapy (HAART) is partially protective and has altered the natural history of HIV-associated kidney disease. Nonetheless, HIVAN remains an important public health concern among HIV-infected African Americans. Although polymorphisms in the MYH9 gene on chromosome 22 are strongly associated with HIVAN, as well as with idiopathic focal segmental glomerulosclerosis and global glomerulosclerosis (historically labeled "hypertensive nephrosclerosis"), the majority of HIV-infected patients who are genetically at risk from MYH9 do not appear to develop severe kidney disease. Therefore, we postulate that additional environmental exposures and/or inherited factors are necessary to initiate human HIVAN. Gene-environment interactions have also been proposed as necessary for initiation of HIVAN in murine models. It is important that these novel risk factors be identified, as prevention of environmental exposures and targeting of additional gene products may reduce the risk for HIVAN, even among those harboring two risk alleles in MYH9.
PMCID: PMC2814053  PMID: 20005488
African Americans; FSGS; HIV-associated nephropathy; kidney disease; MYH9
14.  Proteinuria in paediatric patients with human immunodeficiency virus infection 
In human immunodeficiency virus (HIV)-infected people kidney disease is as an important cause of morbidity and mortality. Clinical features of kidney damage in HIV-infected patients range from asymptomatic microalbuminuria to nephrotic syndrome. The lack of specific clinical features despite the presence of heavy proteinuria may mask the renal involvement. Indeed, it is important in HIV patients to monitor renal function to early discover a possible kidney injury. After the introduction of antiretroviral therapy, mortality and morbidity associated to HIV-infection have shown a substantial reduction, although a variety of side effects for long-term use of highly active antiretroviral therapy, including renal toxicity, has emerged. Among more than 20 currently available antiretroviral agents, many of them can occasionally cause reversible or irreversible nephrotoxicity. At now, three antiretroviral agents, i.e., indinavir, atazanavir and tenofovir disoproxil fumarate have a well established association with direct nephrotoxicity. This review focuses on major causes of proteinuria and other pathological findings related to kidney disease in HIV-infected children and adolescents.
PMCID: PMC3845933  PMID: 24303454
Human immunodeficiency virus-infection; Nephropathy; Proteinuria; Antiretroviral therapy; Children
15.  Nephrotoxicity of HAART 
AIDS Research and Treatment  2011;2011:562790.
Highly active antiretroviral therapy (HAART) and other medical therapies for HIV-related infections have been associated with toxicities. Antiretroviral therapy can contribute to renal dysfunction directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or indirectly via drug interactions. With the increase in HAART use, clinicians must screen patients for the development of kidney disease especially if the regimen employed increases risk of kidney injury. It is also important that patients with chronic kidney disease (CKD) are not denied the best combinations, especially since most drugs can be adjusted based on the estimated GFR. Early detection of risk factors, systematic screening for chronic causes of CKD, and appropriate referrals for kidney disease management should be advocated for improved patient care. The interaction between immunosuppressive therapy and HAART in patients with kidney transplants and the recent endorsement of tenofovir/emtricitabine by the Centers for Disease Control (CDC) for preexposure prophylaxis bring a new dimension for nephrotoxicity vigilance. This paper summarizes the common antiretroviral drugs associated with nephrotoxicity with particular emphasis on tenofovir and protease inhibitors, their risk factors, and management as well as prevention strategies.
PMCID: PMC3157198  PMID: 21860787
16.  Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors 
Kidney disease is an important complication in HIV infected people, and this may be related to infection or antiretroviral therapy (ART). Our aim is to assess renal function in HIV infected paediatric patients, who may be particularly affected and are likely to take ART for longer than adults, and investigate the long term role of Tenofovir Disoproxil Fumarate (TDF) alone or co-administered with Ritonavir-boosted Protease Inhibitors (PI).
Serum creatinine, phosphate and potassium levels, with estimated Glomerular Filtration Rate (eGFR), had been prospectively evaluated for 2 years in a cohort of HIV infected children and adolescents (age 9-18) on ART, and data analyzed according to the exposure to TDF or simultaneous TDF and PI.
Forty-nine patients were studied (57% female, mean age 14). Sixty-three percent were treated with ART containing TDF (Group A), and 37% without TDF (Group B); 47% with concomitant use of TDF and PI (Group C) and 53% without this combination (Group D). The groups didn't differ for age, gender or ethnicity. The median creatinine increased in the entire cohort and in all the groups analyzed; eGFR decreased from 143.6 mL/min/1.73 m2 at baseline to 128.9 after 2 years (p = 0.006) in the entire cohort. Three patients presented a mild eGFR reduction, all were on TDF+PI. Phosphatemia decreased significantly in the entire cohort (p = 0.0003) and in TDF+PI group (p = 0.0128) after 2 years. Five patients (10%) developed hypophosphatemia (Division of Acquired Immune Deficiency AE grade 1 or 2), and four of them were on TDF+PI.
Renal function decrease and hypophosphatemia occur over time in HIV infected children and adolescents on ART. The association with co-administration of TDF and PI appears weak, and further studies are warranted.
PMCID: PMC3306735  PMID: 22269183
17.  Renal Function Declines More in Tenofovir- than Abacavir-Based Antiretroviral Therapy in Low-Body Weight Treatment-Naïve Patients with HIV Infection 
PLoS ONE  2012;7(1):e29977.
To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection.
We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART.
The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model.
The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152–2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339–3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494–5.139; p = 0.001) (61–68 kg: adjusted HR = 1.908; 95%CI, 0.764–4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318–3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003).
The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.
PMCID: PMC3252345  PMID: 22242194
18.  Determining the prevalence of Human Immunodeficiency Virus–Associated nephropathy (HIVAN) using proteinuria and ultrasound findings in a Nigerian paediatric HIV population 
HIV associated nephropathy (HIVAN) is the most common form of chronic kidney disease resulting directly from HIV infection. The true prevalence of HIVAN in the paediatric population of West Africa is unknown, largely due to lack of surveillance and reporting of kidney disease in HIV positive patients.
This was a prospective study over a six month period( July to December 2008) conducted in the Infectious Disease Unit of the Department of Paediatrics, University of Uyo Teaching Hospital, Uyo, Nigeria involving all confirmed cases of paediatric HIV infection. Urine microalbuminuria using calculated urine albumin – creatinine ratio was determined and repeated in 4 weeks interval. CD4 count and renal ultrasonography was done for all the patients. The correlation of urine albumin – creatinine ratio with CD4 count, duration of treatment with highly active antiretroviral therapy (HAART) and association with clinical staging of the disease was also examined.
Fifty – nine (60.2%) were males, thirty – nine (39.8%) were females with male to female ratio of 1.5:1. The prevalence rate of 31.6% HIVAN was found, out of which 3.1% had abnormal ultrasound findings. There was a significant correlation between CD4 count and urine albumin – creatinine ratio (r=−0.22, p=0.03). There was no correlation between urine albumin – creatinine ratio and duration on HAART (r=−0.10, p=0.31).
Screening for microalbuminuria is essential for the early diagnosis and treatment of HIVAN in this age group.
PMCID: PMC3283028  PMID: 22368756
HIVAN; microalbuminuria; HIV; HAART; proteinuria; paediatrics; Nigeria
19.  Neuroimaging studies of the aging HIV-1-infected brain 
Journal of neurovirology  2012;18(4):291-302.
Highly active antiretroviral therapy (HAART) has increased life expectancy among HIV-infected individuals, and by 2015, at least half of all HIV-infected individuals will be over 50 years of age. Neurodegenerative processes associated with aging may be facilitated by HIV-1 infection, resulting in premature brain aging. This review will highlight brain abnormalities in HIV patients in the setting of aging, focusing on recent neuroimaging studies of the structural, physiological, functional and neurochemical changes. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy studies performed during the pre-HAART era or on antiretroviral-naive subjects suggest an accelerated aging process, while those on HAART-treated subjects suggest premature brain atrophy. Diffusion tensor imaging studies yielded conflicting findings on the relationship between HIV and age in neuroasymptomatic individuals. Functional MRI studies found evidence of premature or accelerated aging processes in the brains of HIV subjects. Lastly, many age-related illnesses such as diabetes, stroke, and depression, as well as comorbid substance abuse, may further exacerbate the aging process in the HIV-infected brain, leading to premature or accelerated age-related brain changes. Given the different pathologic or physiologic changes in the brain assessed by the different neuroimaging techniques, using a multimodal approach in longitudinal follow-up studies is recommended for future studies.
PMCID: PMC3931913  PMID: 22653528
Aging; HIV; MRI; PET; Neuroimaging
20.  Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care 
AIDS (London, England)  2012;26(15):1907-1915.
To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.
Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.
Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.
ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.
PMCID: PMC3531628  PMID: 22824630
antiretroviral therapy; chronic kidney disease; tenofovir
21.  Treatment of Recurrent Hepatocellular Carcinoma with Sorafenib in a HIV/HCV Co-Infected patient in HAART: A Case Report 
Liver disease is the second cause of death among HIV patients receiving highly active antiretroviral therapy (HAART) in Europe. HIV patients have a high prevalence of chronic HBV (6–10%) and HCV (33%) co-infection, and accelerated progression of viral hepatitis. Furthermore, the long duration of both HIV and HCV diseases in the HAART era increases the risk of hepatocellular carcinoma.
We report the case of a 49 year -old HIV/HCV co-infected male patient who developed hepatocellular carcinoma. The patient underwent a partial hepatectomy, and a few months later was treated with transcatheter arterial chemoembolisation due to hepatocarcinoma recurrence. Two months later, advanced hepatocellular carcinoma was diagnosed and sorafenib therapy was initiated. The patient achieved partial response of the main lesions, complete regression of the smallest lesions and did not experience clinical progression during the 20-month follow-up period. During therapy with sorafenib, the patient was treated with HAART with good viral and immunological responses. We used the therapeutic drug monitoring to assess antiretroviral concentrations during co-administration of sorafenib. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines. No grade 3 or 4 toxicities were observed. At month 20 of treatment, new liver lesions with portal vein thrombosis were diagnosed. After 28 months of sorafenib therapy, the patient deceased for severe liver insufficiency.
Sorafenib monotherapy demonstrated a marked delay in HCC disease progression in an HIV/HCV co-infected patient. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines, suggesting a possible interaction.
PMCID: PMC3508865  PMID: 22741810
HAART; Sorafenib; Fosamprenavir; TDM; Hepatocarcinoma; HIV/HCV co-infection
22.  Is Antiretroviral Therapy Causing Long-Term Liver Damage? A Comparative Analysis of HIV-Mono-Infected and HIV/Hepatitis C Co-Infected Cohorts 
PLoS ONE  2009;4(2):e4517.
The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of −0.46% (−1.61% to 0.71%) in HIV mono-infected compared to 2.54% (−1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.
PMCID: PMC2637977  PMID: 19223976
23.  Motor Function and Human Immunodeficiency Virus-Associated Cognitive Impairment in a Highly Active Antiretroviral Therapy-Era Cohort 
Archives of neurology  2008;65(8):1096-1101.
Cognitive impairment has long been recognized as a manifestation of human immunodeficiency virus (HIV) infection. However, highly active antiretroviral therapy (HAART) has altered the neurologic manifestations of HIV.
To develop a measure to quantify the motor abnormalities included in the original descriptions of HIV-associated dementia (HAD); to determine whether motor, affective, and behavioral dysfunction predict cognitive impairment; and to determine whether quantitative motor testing is a helpful adjunct in the diagnosis of HAD in a complex population from the HAART era.
Neurologic and neuropsychological data were collected from the Manhattan HIV Brain Bank, a longitudinal cohort study of patients with advanced HIV. The HIV-Dementia Motor Scale (HDMS) was developed and validated and cognitive and affective or behavioral function was quantified using global neuropsychological T scores, the Beck Depression Inventory (BDI), and an independent assessment of apathy. Relationships among cognitive, motor, affective, and behavioral performance were examined using correlation, linear regression, and analyses of variance.
An urban AIDS research center.
A total of 260 HIV-positive, predominantly minority patients.
Main Outcome Measures
The HDMS scores and global neuropsychological T scores.
The HDMS and BDI scores were independent predictors of cognitive impairment. Significant cognitive impairment was found in patients with motor dysfunction. Patients diagnosed as having HAD had a greater degree of motor impairment than those with other neurocognitive diagnoses.
Motor, affective, and behavioral abnormalities predict cognitive impairment in HIV-positive patients in this HAART-era cohort. The HDMS may be useful in the assignment of HIV-associated neurocognitive impairment in HIV populations in which normative data or neuropsychological test design is not optimal.
PMCID: PMC2696223  PMID: 18695060
24.  Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study 
BMC Infectious Diseases  2013;13:301.
The aim of this study was to investigate the impact of a tenofovir disoproxil fumarate (TDF) plus ritonavir-boosted protease inhibitor (PI/r) regimen on renal function in Chinese HIV-infected patients.
Seventy-five HIV-1 infected patients failing first-line antiretroviral therapy (ART) comprised the TDF+PI/r group. Seventy-five HIV-1 infected patients matched for gender, age, and renal function made up the control. All subjects completed follow-up visits over 48 weeks. CD4 cell count, plasma HIV-1 viral load, and urine protein level were assessed at the trial start (baseline, week 0) and at week 48. The serum creatinine and estimated glomerular filtration rate (eGFR) were monitored at each follow-up point. Change in eGFR from baseline to week 48 was also compared.
Compared to control, the TDF+PI/r group exhibited higher levels of serum creatinine (79 vs. 69.7 μmol/L, P<0.001) and a lower rate of eGFR (93.0 vs. 101.6 ml/min/1.73m2, P=0.009) at the end of week 48. Patients treated with TDF+PI/r showed greater decline in eGFR than control (−8.8 vs. 6.4ml/min/1.73m2, P<0.001). Compared to baseline renal function of the control group, the TDF+PI/r group exhibited a greater median decline in eGFR at the end of week 48 (P<0.001).
We found that a TDF+PI/r based ART regimen resulted in greater renal function decline over 48 weeks. Therefore, renal function should be monitored especially when TDF is used in combination with PI/r.
Trial registration identifier: NCT00872417
PMCID: PMC3707768  PMID: 23815472
Antiretroviral Therapy; HIV; Renal Function; Tenofovir; Protease Inhibitor
25.  Sorafenib Therapy for Hepatocellular Carcinoma in an HIV–HCV Coinfected Patient: A Case Report 
The Oncologist  2010;15(2):142-145.
The paper reports on the coadministration of highly effective antiretroviral therapy and sorafenib for hepatocellular carcinoma in a patient coinfected with HIV and hepatitis C virus. The simultaneous administration of these therapies was well tolerated and effective.
HIV and hepatitis C virus (HCV) share common modes of transmission, resulting in about 33% incidence of coinfection among people infected with HIV. The survival benefit from highly effective antiretroviral therapy (HAART) for HIV infection is resulting in an increased incidence of hepatocellular carcinoma (HCC) in this population. There are no reports to date regarding the coadministration of HAART and sorafenib for hepatocellular carcinoma.
We report the case of a 42-year-old male patient coinfected with HIV and HCV who developed advanced HCC not amenable to curative therapy. The patient was treated with sorafenib, an oral multikinase inhibitor shown to lead to a longer median survival time and time to progression in patients with advanced HCC. Antiretroviral therapy was continued during sorafenib therapy.
The patient achieved a partial tumor response after 3 months and continued to respond at subsequent assessments. His serum α-fetoprotein normalized from 2,172 IU/ml to 2 IU/ml. He had durable stable disease after 23 months of therapy. Antiretroviral therapy was efficacious (CD4+ lymphocyte count, 377/μl; HIV viremia, <50 copies/ml). The simultaneous administration of these therapies was well tolerated. No grade 3 or 4 toxicities were observed. Exacerbation of pre-existing hypertension, grade 2 diarrhea, and grade 1 skin reaction were observed.
This is the first report in which sorafenib has been successfully used to treat HCC in a patient with HIV–HCV coinfection.
PMCID: PMC3227942  PMID: 20142333
Hepatocellular carcinoma; HIV; HCV; Coinfection; Sorafenib

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