Weeks Of Antiretroviral Treatment Research Articles

Serum ghrelin and obestatin levels in HIV-infected patients: Effect of 36 weeks of antiretroviral treatment

IntroductionPatients with HIV+ often present lipid disturbances. The role of ghrelin and obestatin in these lipid disturbances is not clear. The effect of antiretroviral (ART) drugs on those molecules is also unknown. This study measured ghrelin and obestatin levels, as well as metabolic markers, in patients with HIV+ before and after 36 weeks of ART. Material and methodsTwenty HIV-positive, ART-naïve patients who started a scheme consisting of tenofovir/emtricitabine+lopinavir/ritonavir were enrolled. Plasma samples were collected before and after 36 weeks of treatment. Serum ghrelin and obestatin levels were quantitated by ELISA; glucose, cholesterol, and triglyceride levels were measured by colorimetric and enzymatic methods, and cardiovascular risk was calculated by the atherogenic index of plasma (AIP). ResultsAll patients completed 36 weeks of ART. Total cholesterol (p<0.001), LDL-C (p=0.019), HDL-C (p=0.003), VLDL-C (p=0.002), and triglyceride levels (p=0.021) significantly increased after treatment. AIP revealed increased cardiovascular risk at baseline, which remained high after treatment. There was a statistically significant increase in obestatin level in the unpaired and paired analyses, while ghrelin levels only showed a trend to increase. Changes in ghrelin and obestatin levels positively correlated, but no correlation was seen with any metabolic parameter. ConclusionAfter 36 weeks of ART, patients showed an altered lipid profile, but there were no significant changes in cardiovascular risk. Ghrelin and obestatin levels increased after 36 weeks of ART, but the increase was only significant for obestatin. Changes in ghrelin and obestatin positively correlate.

Serum ghrelin and obestatin levels in HIV-infected patients: Effect of 36 weeks of antiretroviral treatment

IntroductionPatients with HIV+ often present lipid disturbances. The role of ghrelin and obestatin in these lipid disturbances is not clear. The effect of antiretroviral (ART) drugs on those molecules is also unknown. This study measured ghrelin and obestatin levels, as well as metabolic markers, in patients with HIV+ before and after 36 weeks of ART. Material and methodsTwenty HIV-positive, ART-naïve patients who started a scheme consisting of tenofovir/emtricitabine+lopinavir/ritonavir were enrolled. Plasma samples were collected before and after 36 weeks of treatment. Serum ghrelin and obestatin levels were quantitated by ELISA; glucose, cholesterol, and triglyceride levels were measured by colorimetric and enzymatic methods, and cardiovascular risk was calculated by the atherogenic index of plasma (AIP). ResultsAll patients completed 36 weeks of ART. Total cholesterol (p<0.001), LDL-C (p=0.019), HDL-C (p=0.003), VLDL-C (p=0.002), and triglyceride levels (p=0.021) significantly increased after treatment. AIP revealed increased cardiovascular risk at baseline, which remained high after treatment. There was a statistically significant increase in obestatin level in the unpaired and paired analyses, while ghrelin levels only showed a trend to increase. Changes in ghrelin and obestatin levels positively correlated, but no correlation was seen with any metabolic parameter. ConclusionAfter 36 weeks of ART, patients showed an altered lipid profile, but there were no significant changes in cardiovascular risk. Ghrelin and obestatin levels increased after 36 weeks of ART, but the increase was only significant for obestatin. Changes in ghrelin and obestatin positively correlate.

Reduced sTWEAK and Increased sCD163 Levels in HIV-Infected Patients: Modulation by Antiretroviral Treatment, HIV Replication and HCV Co-Infection

BackgroundPatients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV.ObjectiveThe aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects.ResultsPatients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations.ConclusionHIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART.

4.0 When to start

4.0 When to start

Can we stop CD4+ testing in patients with HIV-1 RNA suppression on antiretroviral treatment?

It is unclear whether regular CD4 testing is necessary for all patients during long-term antiretroviral treatment, after patients achieve full HIV-1 RNA suppression. In the AntiRetroviral Therapy with TMC114 Examined in Naïve Subjects (ARTEMIS) trial, 689 treatment-naïve patients were randomized to tenofovir/emtricitabine and either darunavir/ritonavir or lopinavir/ritonavir. The number of patients with CD4 cell counts equal or above 200 copies/ml and HIV-1 RNA below 50 copies/ml at week 48 was assessed. For these patients, we assessed whether CD4 cell counts fell below 200 cells/μl from week 49 to week 192, while HIV-1 RNA suppression was maintained. Of the 520 responders, five (1.0%) progressed to an AIDS-defining event during the first 48 weeks of the trial, whereas 19 of the 169 non-responders (11.2%) developed AIDS-defining events during this time (P = 0.001, Fisher's Exact test). Of the 449 patients with sustained HIV-1 RNA suppression below 400 copies/ml from week 49 to week 192, five patients (1.1%) had reductions in CD4 cell count below 200 cells/μl on two consecutive visits. These were all short-term reductions, with follow-up results equal or above 200 cells/μl. There was a benefit to testing for CD4 cell count in the first 48 weeks of treatment, to identify patients who have immuno-virological discordance and therefore a higher risk of progression to AIDS. However, after 48 weeks of antiretroviral treatment, for the 'responder' patients in the ARTEMIS trial who had both HIV-1 RNA below 50 copies/ml and rises in CD4 cell count equal or above 200 cells/μl, there appears to be little clinical benefit from continued testing for CD4 cell count.

No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial.

The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count < 350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p < 0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p < 0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.

Successful drug treatment of immune reconstitution disease with the leukotriene receptor antagonist, montelukast: a clue to pathogenesis?

Immune reconstitution disease (IRD) is a common clinical syndrome that typically presents as symptoms developing within a few weeks of starting antiretroviral therapy [1]. The pathogenesis is not fully understood, but is thought to relate to changes in the immune response directed against local antigen [2]. Even when there is no obvious specific trigger, the symptoms can be prolonged and severe [3]. Treatment is often with steroids, which carry a degree of risk in an HIV-infected population [4]. A recent report highlighted the potential value of the leukotriene receptor antagonist, montelukast, in IRD [5]. Here we describe its use in a case of urticarial vasculitis associated with antiretroviral therapy. A 59-year-old HIV-infected Caucasian man was started on a nucleoside-sparing regimen of saquinavir and lopinavir with ritonavir boosting 5 months after a voluntary break from treatment. Previously, he had been almost 100% adherent to therapy, and had attained an 800 cells/μl blood CD4 cell count increase from a nadir of 36 cells/μl. At the time of recommencing HAART his blood CD4 cell count, however, had declined to 226 cells/μl and his HIV load had risen to 34 751 viral copies/ml. He was reviewed after 3 weeks of antiretroviral treatment with a one day history of a morbilliform, urticarial rash predominantly affecting his legs, buttocks and arms (Fig. 1). His blood CD4 cell count was unchanged at 236 cells/μl, although his plasma viral load had reduced to 221 copies/ml.Fig. 1: Urticarial rash after 3 weeks of antiretroviral therapy.Blood tests indicated a raised C-reactive protein (CRP) level of 79 mg/l (normal < 5 mg/l), a white cell count of 20.1 × 109/l (normal range 3.0–10.0 × 109/l) and neutrophilia of 14.7 × 109/l (1.5–7.4 × 109/l). Serology for syphilis, rubella, measles and parvovirus B19 demonstrated no active infection. Complement and anti-C1q antibody levels were normal and an autoimmune screen was negative. Symptomatic treatment with antihistamines (cetirizine and ranitidine) was initiated. He was adherent to all of his medication but re-attended 2 weeks later with increasing malaise, worsening rash, fevers, diarrhoea and arthralgia. The serum CRP level was elevated at 199 mg/l, white cell count 17.2 × 109/l and neutrophils 13.9 × 109/l. Renal function was normal. A skin biopsy revealed a perivascular inflammatory cell infiltrate with leukocytoclasia suggestive of a vasculitic process. He continued his antiretroviral drugs and was commenced on 40 mg oral prednisolone with a presumptive diagnosis of IRD-associated urticarial vasculitis. His symptoms resolved and his inflammatory markers returned to normal. Two days after completing a total of one month's reducing steroid course, the rash and arthralgia returned associated with fever and tachycardia. Blood work again showed an acute rise in his white cell count and CRP (to 150 mg/l). He continued his antiretroviral drugs, and therapy with oral montelukast 10 mg daily was initiated. He noted an immediate improvement, and within 5 days his symptoms and signs had settled (including resolution of the increased inflammatory markers). Montelukast was discontinued after 3 months with no untoward effects. Over this time his HIV load became undetectable (< 50 viral copies/ml) and his blood CD4 cell count doubled. Although the diagnosis of IRD is currently clinical (and thus open to some overinterpretation), we believe the time course of this patient's symptoms together with the associated fall in the HIV load is consistent with IRD. He responded rapidly to treatment with steroids and subsequently with montelukast, adding to the evidence base for the use of the latter drug in the management of HIV-related IRD [5]. The pathological mechanism of IRD remains to be determined [6]. In this case of urticarial vasculitis the dramatic effect of montelukast suggests a role for excessive leukotriene activity in its development. Leukotrienes exert broad proinflammatory effects, including leukocyte recruitment to sites of inflammation and the promotion of innate immune responses via the stimulation of cytokines and chemokines [7]. They may also be deficient in advancing HIV infection [8]. We propose that montelukast, acting as a partial agonist, attenuates an over-vigorous leukotriene-driven inflammatory response due to antiretroviral therapy without causing significant immunosuppression itself. Although one cannot yet predict who will respond to drug therapy, or the duration of treatment required, we believe that montelukast may be useful in the treatment of IRD and warrants further study.

Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme

We read with interest the recent paper by Lortholary et al. describing cryptococcocal immune reconstitution disease (IRD) in France. This is an increasingly recognized complication of the initial weeks of antiretroviral treatment (ART). However to our knowledge the frequency of cryptococcocal IRD in low-income countries has not previously been reported. We run a community-based ART programme in Gugulethu Cape Town South Africa. Between September 2002 and November 2004 434 treatmentnaive patients started triple-drug ART according to WHO 2002 treatment guidelines. The patients mean age was 34 years their median blood CD4 cell count was 86 cells/µl [interquartile range (IQR) 46-146 cells/µl] and the median plasma HIV load was 76 337 copies/ml (IQR 32 723-192 772 copies/ml). A total of 137 patients (32%) had WHO stage 4 disease and among these cryptococcal meningitis was the AIDS-defining illness in 18 (13%). These diagnoses were made a median of 7 months (range 2-24 months) before the initiation of ART. According to national guidelines cryptococcal meningitis was treated with fluconazole 400 mg/day for 8 weeks followed by 200 mg/day as secondary prophylaxis. (excerpt)

The 48-week efficacy of once-daily saquinavir/ritonavir in patients with undetectable viral load after 3 years of antiretroviral therapy

To evaluate the efficacy and safety of once-daily saquinavir-soft-gel-capsules/ritonavir (SQV-SGC/RTV) 1600 mg/100 mg plus dual nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-infected patients with plasma viral load (pVL) <50 HIV-1 RNA copies/mL following 3 years of antiretroviral therapy. A total of 69 patients with pVL <50 copies/mL after 162 weeks of antiretroviral treatment started SQV-SGC/RTV 1600 mg/100 mg once-daily while continuing dual NRTIs. Previous treatment consisted of 66 weeks of treatment with a half/full dose of zidovudine (ZDV)/zalcitabine (ddC), followed by 2 years of SQV-SGC twice a day (bid) plus ZDV/lamivudine (3TC) or didanosine (ddI)/stavudine (d4T). Efficacy (pVL), safety and immunological changes (CD4 cell counts) were evaluated after 48 weeks in this open-label, single-arm prospective study. SQV-SGC/RTV once-daily was well tolerated. No patient changed regimens or was lost to follow-up. After 48 weeks, 63 of 69 patients (91%) had pVL <50 copies/mL (five of the six remaining patients had pVL <400 copies/mL, and one patient had an unexplained rise to 39 500 copies/mL, which decreased to <50 copies/mL 12 weeks later). Median CD4 count increased from 534 cells/muL at the start of the SQV-SGC/RTV once-daily treatment to 664 cells/muL (P<0.001). Compared to the preceding 48 weeks on bid SQV-SGC, the CD4 cell count improved significantly on once-daily SQV-SGC/RTV (P<0.001). These data support the use of SQV-SGC/RTV 1600 mg/100 mg once-daily with two NRTIs as a convenient, safe and cost-saving regimen to maintain viral suppression and CD4 counts for 48 weeks in this preselected cohort on highly active antiretroviral therapy (HAART) with pVL <50 copies/mL. The CD4 count rise may be a result of continued immune reconstitution in patients with well-controlled infection.

Recurrence of post‐traumatic stress disorder symptoms after initiation of antiretrovirals including efavirenz: a report of two cases

Some antiretrovirals has been reported to cause a wide range of psychiatric symptoms. However, reappearance of post-traumatic stress disorder (PTSD) symptoms has not been described in relation to these medications. Case report. The Boston Medical Center, a tertiary care academic centre. Two HIV-infected refugees re-experienced symptoms of PTSD after starting therapy with efavirenz (EFV) and zidovudine (ZDV). The two patients had no typical factors present to account for the PTSD exacerbation. In both patients, the symptoms of PTSD gradually subsided to baseline within the first 4 weeks of antiretroviral treatment. We believe that EFV, a non-nucleoside reverse transcriptase inhibitor, with ZDV, may be manifesting its known neuropsychiatric toxicities in a heretofore unreported presentation of PTSD exacerbation.