Pablo Rivas

Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir.

Background:Tenofovir (TDF) is the most widely prescribed antiretroviral drug. Kidney abnormalities are the main concern using the drug. As glomerular function is infrequently affected in patients treated with TDF, herein, we report the results of an extensive examination of tubular function. Methods:Cross-sectional study of plasma and 24 h urine markers of kidney tubulopathy (glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria and β2-microglobulinuria) could be allocated in three groups: patients under a TDF-containing HAART; patients on HAART never exposed to TDF; and antiretroviral-naive individuals. Significant tubular damage was defined when at least two of these parameters were repeatedly present, being at least one part of the Fanconi syndrome criteria (glucosuria, hyperaminoaciduria and hyperphosphaturia). Glomerular function was assessed using creatinine clearance. Results:A total of 284 consecutive HIV patients were examined, 154 on TDF, 49 on other HAART regimens and 81 drug-naive. No significant differences in creatinine clearance were observed when comparing distinct groups. The proportion of patients with tubular damage in groups 1, 2 and 3 were 22, 6 and 12%, respectively. In a multivariate analysis [odds ratio (OR) {95% confidence interval (CI)} P], the only independent predictors of tubular dysfunction were TDF use (21.6, 4.1–113, <0.001) and older age (1.1 per year, 1.0–1.1, 0.01). Conclusion:Exposure to TDF is associated with an increased risk over time of kidney tubular abnormalities in the absence of significant impaired glomerular function. Although long-term consequences of this tubulopathy are unknown, close monitoring of accelerated bone mineral loss and renal insufficiency are warranted. Periodic screening of tubular function parameters should be recommended to patients receiving TDF.

Severe liver disease associated with prolonged exposure to antiretroviral drugs

Background: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. Methods: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. Results: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. Conclusions: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients

Objectives:To assess the effect of early syphilis on HIV viral load (VL) and CD4 cell count in patients with HIV and to analyze factors associated with changes in HIV VL and CD4 cell count. Design:Multicenter study of a series of patients with HIV who were diagnosed with early syphilis infection during 2004 through 2005. Patients who started or changed their highly active antiretroviral therapy (HAART) regimen during the analysis period were excluded. Results:One hundred eighteen patients were analyzed: 95.8% were men, mean patient age was 38.2 years, 83.9% were homosexual men, 50.8% were on antiretroviral therapy at the time syphilis was diagnosed, and HIV and syphilis diagnoses were coincident in 38 (32.2%) cases. CD4 cell counts were lower during syphilis than before (590 vs. 496 cells/μL; P = 0.0001) and after syphilis treatment (509 vs. 597 cells/μL; P = 0.0001). The HIV VL increased in 27.6% of patients during syphilis. The only factor associated with an HIV VL increase was not being on HAART, and the only factor associated with a CD4 count decrease >100 cells/μL during syphilis was the prior CD4 cell count. Conclusions:Syphilis infection was associated with a decrease in the CD4 cell count and an increase in the HIV VL in almost one third of the patients. In this series, more than two thirds of the syphilis cases were diagnosed in patients who were previously known to be infected with HIV.

Predictors of Liver Fibrosis in HIV-Infected Patients with Chronic Hepatitis C Virus (HCV) Infection: Assessment Using Transient Elastometry and the Role of HCV Genotype 3

BACKGROUND Liver fibrosis is accelerated in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The reasons for this faster liver disease progression are unclear, although higher plasma HCV RNA levels and distinct HCV genotype distribution in this population, compared with in HCV-monoinfected subjects, could play a role. METHODS Liver fibrosis was assessed using elastometry in all consecutive HIV-infected patients with chronic hepatitis C who attended our institution (Hospital Carlos III, Madrid) during the past 12 months. Hepatic stiffness was measured in kiloPascal units (kPa) and was interpreted on the basis of Metavir score: no or mild fibrosis (score, F0-F1) when liver stiffness is < or =7.1 kPa, and fibrosis with septa or cirrhosis (F2-F4) when >7.1 kPa. RESULTS A total of 283 patients (71% were male; mean age, 42 years; 94% were injection drug users and 94% were receiving antiretrovirals; mean CD4 cell count, 554 cells/microL; 72% with plasma HIV RNA level of <50 copies/mL) were analyzed. The mean alanine aminotransferase level was 68 IU/L, and the mean plasma HCV RNA level was 5.9 log IU/mL. HCV genotype distribution was as follows: genotype 1, 60% of patients; genotype 2, 2%; genotype 3, 26%; and genotype 4, 12%. Overall, 164 (58%) of the patients had scores indicating advanced liver fibrosis (F2-F4), as determined using elastometry. In the univariate and multivariate analyses, respectively, a significant odds ratio (OR) for score F2-F4 was found for HCV genotype 3, compared with the other genotypes (OR, 1.9 [95% confidence interval {CI}, 1.1-3.4] vs. 4.3 [95% CI, 1.4-13.3]); for older age (OR, 1.1 [95% CI, 1.03-1.17] vs. 1.1 [95% CI, 1.01-1.25]); and for elevated alanine aminotransferase levels (OR, 1.02 [95% CI, 1.01-1.03] vs. 1.03 [95% CI, 1.01-1.04]). Although patients with HCV genotype 1 had higher mean serum HCV RNA levels than did those with HCV genotype 3 (6.1 log IU/mL vs. 5.7 log IU/mL; P=.01), patients with HCV genotype 3 tended to have F2-F4 scores more frequently than did those with HCV genotype 1 (69% vs. 58%; P = not significant). CONCLUSIONS HCV genotype 3, older age, and elevated alanine aminotransferase levels are independent predictors of advanced liver fibrosis in HCV-HIV-coinfected patients.

Incidence of liver cirrhosis in HIV-infected patients with chronic hepatitis B or C in the era of highly active antiretroviral therapy.

BACKGROUND Longitudinal assessment of liver fibrosis with transient elastometry (TE) in patients with chronic viral hepatitis is becoming routine clinical practice in many clinics, as this procedure is non-invasive, easy to perform and relatively inexpensive, allowing early detection of cirrhosis. Herein, we examine the incidence of cirrhosis, using TE assessment, in HIV-infected individuals with chronic hepatitis B or C receiving highly active antiretroviral therapy (HAART). METHODS A longitudinal study was performed on a cohort of HIV-infected patients with chronic hepatitis B or C who were followed since 2004 at Hospital Carlos III (Madrid, Spain) with periodic TE assessments. The primary outcome was the development of cirrhosis, defined as liver stiffness >12.5 KPa. RESULTS A total of 508 HIV-infected patients were examined, of whom 54 developed liver cirrhosis during a mean ±(SD) follow-up of 2.6 ±1.0 years (overall incidence was 41.13 cases per 1,000 person-years). The risk of developing cirrhosis was significantly higher in 297 HCV-RNA-positive patients (either untreated or non-responders to hepatitis C therapy) compared with 55 patients who had cleared HCV with therapy (odds ratio 3.73, 95% confidence interval 1.06-13.17; P=0.04). By contrast, the risk of developing cirrhosis was low and similar in 24 HIV-HBV-coinfected patients under long-term suppressive HBV therapy (mainly tenofovir disoproxil fumarate), 132 HIV-infected patients without chronic liver disease and those who had cleared HCV with therapy. CONCLUSIONS Development of liver cirrhosis in HIV-infected individuals in the HAART era is mainly associated with active HCV coinfection. The risk of developing cirrhosis is negligible in patients who cleared HCV with therapy, as well as in HIV-HBV-coinfected patients on long-term suppressive tenofovir disoproxil fumarate therapy.

Performance of OraQuick Advance® Rapid HIV-1/2 Antibody Test for detection of antibodies in oral fluid and serum/plasma in HIV-1+ subjects carrying different HIV-1 subtypes and recombinant variants

BACKGROUND Rapid, simple, low-cost, sensitive, and specific tests are needed to detect antibodies to all HIV-1 subtypes, especially in developing countries. OBJECTIVE To evaluate the performance of a rapid diagnostic test for detection of HIV-1/2 antibodies in oral fluids and sera/plasma from subjects from geographic areas infected with different HIV-1 variants. STUDY DESIGN OraQuick Rapid HIV-1/2 Diagnostic Test was evaluated in sera and oral fluids from 100 subjects from Spain and South-America. It was also assessed in 56 plasma and 39 oral fluid specimens from 56 Africans carrying HIV-1 non-B subtypes or inter-subtype recombinants defined by phylogenetic analysis at pol and gp41 coding regions. All patients were previously diagnosed as HIV-1 positive by serological tests (Abbott AxSYM HIV-1/2; Western Blot HIV-1/HIV-2 and Pepti-LAV, BIO-RAD). RESULTS OraQuick provided positive results in all 156 serum/plasma specimens regardless of the infecting HIV-1 subtype, and in 136/139 (97.8%) oral fluids. The three oral specimens (2.2%) that yielded false-negative results by OraQuick were taken from one subtype B-infected Spaniard and from two subtype D-infected Africans. The last two were also negative by Pepti-LAV using plasma samples. Ten additional sera and 32 oral fluids from HIV-negative individuals yielded negative results by OraQuick. This rapid test showed good sensitivity for detecting anti-HIV-1 antibodies in oral fluids and in serum/plasma specimens from subjects carrying different HIV-1 subtypes and recombinant variants. CONCLUSION OraQuick demonstrated its utility for detecting infections due to HIV-1 subtypes and recombinants common in developing countries.

Liver Fibrosis in HIV-Infected Patients with Chronic Hepatitis B Extensively Exposed to Antiretroviral Therapy with Anti-HBV Activity

Abstract Purpose: The extent and predictors of liver fibrosis were examined in a HIV/HBVcoinfected cohort with extensive exposure to anti-HBV active HAART. Method: Liver fibrosis was measured using transient elastography. Results: Thirty-seven patients of a median age of 43 were included in the study. All but 2 patients had received anti-HBV drugs for a median time of 40 months in the context of HAART. F0-F1 METAVIR fibrosis scores (minimal or no fibrosis) as measured by elastography were found in 21 (57%) patients. AST levels were significantly lower among F0-F1 patients (33 IU/L) compared to F2-F4 patients (48 IU/L) (p = .01). ALT levels were also lower in F0-F1 patients (38 IU/L) than in F2-F4 patients (54 IU/L) (p = .05). Conclusion: In this HIV/HBV-coinfected cohort, with extensive HAART exposure including anti-HBV agents, more than half of the patients had no or minimal liver fibrosis. Higher transaminase levels were recognized in patients with higher degree of fibrosis.

Clinical Differences and Viral Diversity between Newly HIV Type 1-Diagnosed African and Non-African Patients in Spain (2005–2007)

Abstract The diagnosis of HIV-1 is increasing in African-born persons residing in Europe. They present a high prevalence of HIV-1 non-B variant infections and of parasitic infections, both of which are infrequent in Western countries. Immigration favors their presence in nonendemic countries. In this study, all newly HIV-diagnosed individuals at an HIV/AIDS and Tropical Medicine reference center in Madrid from 2005 through 2007 were retrospectively studied. HIV-1 subtyping was performed in gag, pol, and gp41 coding regions by phylogenetic analyses. The presence of other pathogens was also evaluated. Furthermore, all HIV-1-infected Africans were screened for parasitic infections. Newly diagnosed HIV-1 subjects included 90 sub-Saharan Africans and 188 non-Africans (116 Spaniards, 13 other Europeans, and 59 Latin Americans). Significantly higher numbers of HIV-1-infected Africans than non-Africans were females, acquired HIV-1 by heterosexual contact, and presented a more advanced clinical CDC stage and criteria for starting antiretroviral therapy in the first clinical visit. They predominantly carried non-B subtype infections, mainly intersubtype recombinants. Half of HIV-1-infected Africans had parasitic infections. CD4(+) T cell counts were lower among Africans than Europeans at the time of HIV-1 diagnosis. At 12 months of follow-up after starting antiretroviral treatment, a significantly lower proportion of Africans than non-Africans achieved undetectable viremia due to their higher loss to follow-up. However, CD4(+) T cell recovery and virological failure rates were similar. Therefore, the profile of African HIV-1-infected immigrants varies widely with respect to Spanish HIV-infected individuals. More advanced immunodeficiency and the coexistence of parasitic diseases and infections with a large diversity of HIV-1 non-B and recombinant variants are expected.

Role of atazanavir in the treatment of HIV infection

Atazanavir (ATV) is one of the latest protease inhibitors (PI) approved for the treatment of HIV infection. The drug has a relatively long-life (~7 h) and large inhibitory quotient which allows once daily administration. It is generally well tolerated and the main side effect is hyperbilirubinemia, since ATV inhibits the hepatic uridin-glucoronyl-transferase. A signature mutation at the protease gene, I50L, may confer loss of susceptibility to the drug. Interestingly, it produces hypersusceptibility to all other PIs. When ATV is pharmacokinetically boosted with ritonavir (r) 100 mg/day, a greater genetic barrier for resistance is achieved, and generally more than 3 major PI resistance associated mutations are needed to result in ATV resistance. In drug-naïve subjects, regimens based on ATV/r have shown non-inferiority compared to lopinavir (LPV)/r (CASTLE study) or fosamprenavir/r (ALERT trial), generally with improved tolerance (less diarrhea and dyslipidemia). Given its good tolerance and convenience, ATV has been proven to be successful as a simplification strategy in switch studies (ie, SWAN and SLOAT) conducted in patients with complete virological suppression under other PI-based regimens. Finally, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens, including LPV/r, in rescue interventions in patients failing other PI regimens (ie, studies AI424-045 and NADIS).

Hepatitis B, C, and D and HIV infections among immigrants from Equatorial Guinea living in Spain.

A total of 1,220 subjects from Equatorial Guinea living in Spain (median age = 41 years; 453 male and 767 female) was examined for antibodies to human immunodeficiency virus (HIV) and Hepatitis B (HBV), C (HCV), and D (HDV) viruses. Extracted RNA and DNA from the positive samples were used to quantify viral load. The prevalence of HIV antibodies, HCV RNA, and HBV surface antigen (HBsAg) was 10.8% (N = 132), 11.6% (N = 141), and 7.9% (N = 96), respectively. The most prevalent HIV variant was CRF02_AG (38.5%; N = 40). HCV genotype 4 (60%; N = 36) and HBV genotype A3 (32%; N = 8) were the hepatitis variants most frequently found. Superinfection with HDV was seen in 20.9% (N = 24) of HBsAg carriers. A control group of 276 immigrants from other sub-Saharan countries showed similar rates of HIV and HBsAg, although no HCV cases were found. Immigrants constitute a major source of HIV and hepatitis viruses in Spain; therefore, it is important that control measures are intensified.