Maria Luisa Montes

Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study).

Objective:This study evaluated maintenance with lopinavir/ritonavir monotherapy vs. continuing lopinavir/ritonavir and 2 nucleosides in HIV-infected patients with suppressed HIV replication. Design:Randomized, controlled, open-label, multicenter, pilot clinical trial. Methods:Adult patients were eligible if they had no history of virologic failure while receiving a protease inhibitor, were receiving 2 nucleosides + lopinavir/ritonavir (400/100 mg b.i.d.) for >1 month and had maintained serum HIV RNA <50 copies/mL for >6 months prior to enrollment. Results:Forty-two patients were randomly assigned 1:1 to continue or stop the nucleosides. At baseline there were no significant differences between groups in median CD4 cells/μL (baseline or nadir), pre-HAART (highly active antiretroviral therapy) HIV log10 viremia, or time with HIV RNA <50 copies/mL prior to enrollment. After 48 weeks of follow-up, percentage of patients remaining at <50 HIV RNA copies/mL (intention to treat, M = F) was 81% for the monotherapy group (95% CI: 64% to 98%) vs. 95% for the triple-therapy group (95% CI: 86% to 100%); P = 0.34. Patients in whom monotherapy failed had significantly worse adherence than patients who remained virally suppressed on monotherapy. Monotherapy failures did not show primary resistance mutations in the protease gene and were successfully reinduced with prerandomization nucleosides. Mean change in CD4 cells/μL: +70 (monotherapy) and +8 (triple) (P = 0.27). Mean serum fasting lipids remained stable in both groups. No serious adverse events were observed. Conclusion:Most of the patients maintained with lopinavir/ritonavir monotherapy remain with undetectable viral load after 48 weeks. Failures of lopinavir/ritonavir monotherapy were not associated with the development of primary resistance mutations in the protease gene and could be successfully reinduced adding back prior nucleosides.

Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis.

Background:The OK04 trial has shown that 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy with 2 nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, it is still uncertain if this experimental strategy can maintain suppression in the long term. Methods:Patients entered this noninferiority trial (upper limit 95% confidence interval: +12%) with no history of virological failure while receiving a protease inhibitor and receiving 2 nucleosides plus lopinavir/ritonavir, with HIV RNA <50 copies per milliliter for more than 6 months. Primary end point was percent of patients without therapeutic failure, defined as confirmed HIV RNA >500 copies per milliliter with exclusion of monotherapy patients who resuppressed to <50 copies per milliliter after resuming baseline nucleosides, or loss to follow-up, or change of randomized therapy other than reinduction. Results:Through 96 weeks, percentage of patient without therapeutic failure was 87% (monotherapy, n = 100) vs. 78% (triple therapy, n = 98; 95% confidence interval: −20% to +1.2%). Percentage with HIV RNA <50 copies per milliliter (intention to treat, missing = failure, reinduction = failure): 77% (monotherapy) vs. 78% (triple therapy). Low-level viral rebound was more frequent in the monotherapy group. Twelve patients in the monotherapy group (12%) needed reinduction with nucleosides. Discontinuations due to adverse events were significantly more frequent in the triple therapy group (8%) than in the monotherapy group (0%); P = 0.003. Conclusions:At 96-week lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. (ClinicalTrials.gov number, NCT00114933).

The natural history of liver cirrhosis in HIV-hepatitis C virus-coinfected patients.

Objective:To provide detailed information about the natural history of HIV–hepatitis C virus (HCV)-coinfected patients with cirrhosis. Methods:Prospective cohort including 340 HIV–HCV-coinfected patients with compensated (n = 248) or decompensated (n = 92) cirrhosis. We evaluated predictors of survival and of first hepatic decompensation. Results:The mortality rate for patients with decompensated and compensated cirrhosis was 27.14 deaths per 100 person-years [95% confidence interval (CI) 18.93–35.35] and 3.98 deaths per 100 person-years (95% CI 2.42–5.54), respectively. Rate of first hepatic decompensation in patients with compensated cirrhosis was 4.62 per 100 persons-years (95% CI 2.91–6.33). In the complete cohort, permanent HAART interruption during follow-up, CD4 cell count nadir and baseline Child-Pugh score (CPS) B or C were significantly associated with shorter survival. In patients with compensated cirrhosis factors significantly associated with decreased survival were having the first hepatic decompensation during follow-up, permanent HAART discontinuation, and CPS B and C at baseline. For patients with compensated cirrhosis, time since diagnosis of HCV infection, CPS B and C and permanent HAART discontinuation were significantly associated with the risk of first hepatic decompensation. Sustained viral response to anti-HCV therapy was not independently associated with better survival in patients with compensated cirrhosis. Conclusion:HIV–HCV-coinfected patients with cirrhosis have a relatively good 3-year survival (87%). In contrast, 2-year survival of patients with decompensated liver cirrhosis is only 50%. Three-year survival was mostly impacted by liver-related factors and HAART maintenance.

Pegylated interferon α2a plus ribavirin versus pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

OBJECTIVES The two currently available types of pegylated interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic properties. It is unclear how these differences affect response to therapy. We compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b, both with ribavirin, against chronic hepatitis C virus (HCV) infection in HIV-infected patients. METHODS From the GESIDA HIV/HCV cohort, we analysed patients treated with peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint was a sustained virological response (SVR). RESULTS Both groups were well matched in baseline characteristics except for a higher frequency of injection drug users in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P = 0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P = 0.04). End-of-treatment response was significantly lower among patients treated with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences were found in SVR between patients treated with peg-IFN-alpha2b and those treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P = 0.655). Therapy was interrupted due to adverse events in 33 (14%) patients treated with peg-IFN-alpha2b and 47 (15%) patients treated with peg-IFN-alpha2a. CONCLUSIONS No differences in effectiveness and safety were found between peg-IFN-alpha2b and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected patients.

HAART is associated with lower hepatic necroinflammatory activity in HIV–hepatitis C virus-coinfected patients with CD4 cell count of more than 350 cells/μl at the time of liver biopsy

Objective:To evaluate the impact of HAART on the liver damage of HIV–hepatitis C virus (HCV)-coinfected patients with relatively preserved immune status. Design:Cross-sectional study of liver biopsies. Methods:HIV–HCV-coinfected patients who underwent liver biopsies and had a CD4 cell count of at least 350 cells/μl at the time of liver biopsy were included. Exclusion criteria included positive hepatitis B surface antigen and prior anti-HCV therapy. Necroinflammatory activity and fibrosis was scored by the Scheuer fibrosis staging system. Steatosis was scored according to the percentage of hepatocytes affected. Logistic regression analysis was used to assess determinants of necroinflammatory activity of at least 3. Results:One hundred and nineteen HIV–HCV coinfected patients were included. In the univariate analysis, alcohol abuse, serum alanine aminotransferase levels, steatosis and a high fibrosis score were significantly associated with higher necroinflammatory activity. In the multivariate analysis, a high level of alanine aminotransferase, advanced fibrosis and absence of HAART were associated with higher necroinflammatory activity. Conclusion:Use of HAART was associated with lower levels of necroinflammatory activity. Necroinflammatory activity was strongly associated with higher fibrosis scores. These results suggest that HAART might decrease hepatitis C activity in HIV–HCV-coinfected patients with CD4 cell count of more than 350 cells/μl.

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus

BACKGROUND & AIMS Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.

Failure of cetirizine to prevent nevirapine-associated rash: a double-blind placebo-controlled trial for the GESIDA 26/01 Study.

ObjectivesRash is the most frequent adverse event associated with nevirapine. The use of antihistamines remains unclear in this setting. A double-blind placebo-controlled study was performed to evaluate the efficacy of cetirizine in the prevention of nevirapine rash. MethodsA multicenter, randomized, double-blind, placebo-controlled clinical trial with cetirizine (10 mg/d × 30 days) was conducted. Inclusion criteria were HIV-1 infection and nevirapine therapy started with any CD4 cell count or plasma viral load and without simultaneous use of abacavir, cotrimoxazole, or rifampin. Clinical follow-up was performed at 15, 30, and 90 days. ResultsTwo hundred seventeen evaluable patients were enrolled (107 patients receiving cetirizine and 110 patients receiving placebo), 32.3% of whom were women. The median baseline CD4 cell count and plasma viral load were 341 cells/mm3 and 11,000 copies/mL, respectively. Overall, 29 rashes (13.4%) were detected: 16 (15.0%) in the cetirizine group and 13 (11.8%) in the placebo group (odds ratio [OR] = 1.31, 95% confidence interval [CI]: 0.60–2.88; P = 0.50). The incidence of moderate to severe rashes leading to nevirapine withdrawal was 10.3% (11 of 107 patients) in the cetirizine group and 7.3% (8 of 110 patients) in the placebo group (OR = 1.46, 95% CI: 0.52–4.18; P = 0.43). Adverse events leading to withdrawal of therapy appeared in 14 patients (13.1%) from the cetirizine group and 10 (9.1%) from the placebo group (P = 0.34). ConclusionCetirizine does not prevent the incidence or affect the severity of nevirapine-associated rash.

Effect of accompanying antiretroviral drugs on virological response to pegylated interferon and ribavirin in patients co-infected with HIV and hepatitis C virus

OBJECTIVES The effects of antiretroviral drugs on the response to pegylated interferon plus ribavirin remain uncertain. We evaluated whether antiretroviral drugs affected the response to pegylated interferon plus ribavirin in patients co-infected with HIV and hepatitis C virus (HCV). METHODS We conducted a retrospective analysis of two cohorts of HIV/HCV-co-infected patients treated with pegylated interferon plus ribavirin between 2001 and 2007 in Spain. The outcome measure was sustained virological response (SVR). Logistic regression models were used to test possible associations between non-response and pre-treatment characteristics, including accompanying antiretroviral drugs. RESULTS The study sample comprised 1701 patients: 63% were infected with HCV genotype (G) 1 or 4 and 88% were taking highly active antiretroviral therapy (HAART). Factors independently associated with increased odds of SVR were G2 or 3, HVC RNA <500,000 IU/mL and CDC clinical category A or B. When we adjusted for these prognostic factors and dose of ribavirin/kg, the adjusted odds ratio (AOR) of SVR for patients without HAART was 1.31 [95% confidence interval (CI) 0.91-1.88; P = 0.144]. Taking the backbone of tenofovir and lamivudine/emtricitabine as a reference, we found that, with the exception of regimens including zidovudine, the effect of other nucleoside reverse transcriptase inhibitor backbones had little effect on SVR. The AOR of SVR for zidovudine and lamivudine was 0.65 (95% CI 0.46-0.93, P = 0.017). We carried out several sensitivity analyses, the results of which were consistent with the findings of the primary analysis. CONCLUSIONS Our results suggest that, with the exception of regimens including zidovudine, accompanying antiretroviral drugs have little effect on the virological response to pegylated interferon plus ribavirin in HIV/HCV-co-infected patients.

Hypertension and isolated office hypertension in HIV-infected patients determined by ambulatory blood pressure monitoring: prevalence and risk factors.

Objective:To determine prevalence and risk factors for hypertension and isolated office hypertension diagnosed by ambulatory blood pressure monitoring in HIV-infected patients. Methods:Cross-sectional study of 310 patients. A 24-hour ambulatory blood pressure monitoring procedure was performed on the nondominant arm in those patients showing office systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Results:Twenty patients (6.5%) had a prior diagnosis of hypertension. Hypertension was confirmed by ambulatory blood pressure monitoring in 26 patients and isolated office hypertension in 17 patients. Isolated office hypertension and hypertension prevalence were 5.5% (95% confidence interval: 3 to 8) and 14.8% (95% confidence interval; 10.8 to 18.8), respectively. Isolated office hypertension was present in 39% of patients with office hypertension. In the univariate analysis, variables significantly associated with hypertension were age, waist circumference, established cardiovascular disease, family history of hypertension, lipoatrophy, metabolic syndrome, duration of infection, CD4 nadir, HIV RNA <50 copies/mL, and antiretroviral treatment. In the multivariate analysis, family history of hypertension [odds ratio (OR): 2.24; P = 0.027], increasing age (OR: 1.08; P < 0.001), and number of different antiretroviral regimens (OR: 1.2; P = 0.001) were associated with hypertension and female gender (OR: 0.27; P = 0.02) had a protective effect. Conclusions:The prevalence of hypertension using ambulatory blood pressure monitoring in HIV-infected patients was 15%. Because isolated office hypertension occurs in 39% of HIV-infected patients with office hypertension, ambulatory blood pressure monitoring could be useful to confirm the diagnosis of hypertension. Hypertension is strongly associated with family history of hypertension, male gender, age, and number of antiretroviral regimens.

Similar effectiveness of direct-acting antiviral against hepatitis C virus in patients with and without HIV infection

Objective: We compared the baseline characteristics, effectiveness, and tolerance of direct-acting antiviral drug (DAA)-based regimens taken by hepatitis C virus (HCV)-monoinfected and HCV/HIV-coinfected individuals in clinical practice. Design: We performed a prospective observational study in two tertiary centres in Madrid, Spain, which included all HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting, from April 2015 to November 2015. We evaluated sustained virological response 12 weeks after the end of therapy (SVR12), adverse events, and baseline and treatment characteristics. Results: The study population comprised 1634 patients: 1152 HCV-monoinfected patients (70%) and 482 HCV/HIV-coinfected patients (30%). Fifty percent had cirrhosis, and 47% were peginterferon/ribavirin-experienced. HCV/HIV-coinfected patients were younger [median age (interquartile range) 51 (48–54) years vs. 59 (50–68) years; P < 0.001), more frequently male (76 vs. 54%; P < 0.001), and infected with genotypes 1a (37 vs. 17%; P < 0.001), 3 (15 vs. 7%; P < 0.001), and 4 (23 vs. 4%; P < 0.001). One of every three patients took ribavirin. SVR12 was 94% (95% confidence interval 91.7–96%) and 97% (95% confidence interval 95.7–99.4%) in coinfected and monoinfected patients, respectively, with no significant differences between the groups after adjustment for cirrhosis, genotype, and DAA combination. DAA-based regimens were well tolerated, and only 1% of patients had severe adverse events, with no differences between the populations. Conclusions: HCV/HIV-infected patients treated with all-oral DAA combinations achieved high rates of SVR12 that were similar to those of HCV-monoinfected patients under real-life conditions. Safety and tolerance were excellent, even in patients with end-stage liver disease.