Summary reports of other studies at BHIVA

HIV Treat Bull - 2008 May-June;9(5/6):8

Simon Collins, HIV i-Base

Effect of 100mg ritonavir once- and twice-daily on lipids and cardiovascular markers in HIV-negative volunteers

Carl Fletcher presented results from a study from the Chelsea and Westminster Hospital looking at the short-term impact of low-dose ritonavir on lipids, CD36 and other vascular inflammation markers (VIM) in 20 HIV-negative volunteers. The study looked at the relationship between drug exposure and these parameters.

Twenty HIV-negative volunteers (10 men and 10 women) were randomised volunteers to receive 100 mg ritonavir either once-daily (OD) or twice-daily (BID) for 14 days, and then, after a short wash-out period, switched to the alternative dose for a further 14 days. Median age and BMI were 28 years (range 19-45) and 22 kg/m² (range 18-26). CD36 is a receptor with a role in cholesterol accumulation and atherosclerosis pathogenesis, that is upregulated by some PIs including full-dose ritonavir. PIs can decrease monocyte CD36 levels in HIV-positive patients. Vascular markers were hsCRP, sICAM-1 and sCD40L. Lipid parameters included TC, HDL, LDL and TG.

They reported significant decreases in HDL and CD36 expression for OD and BID dosing (see Table 1) but only a significant increase in triglycerides with the BID dose. No changes in hs-CRP and VIM were observed. Drug levels showed a wide range of inter-patient variability, but there was a significant correlation between RTV plasma exposure and the change in TG and HDL (r=0.34, p=0.030 and r=0.33, p=0.040, all subjects).

Table 1: Ritonavir exposure and impact on lipids and other markers

This study was also presented at the Retrovirus conference in Boston in February.

Ref: Fletcher C et al. Plasma exposure of 100mg once (OD) and Twice (BID) decreases HDL and CD36 expression but only BID dosing increases triglycerides: potential impact of RTV on cardiovascular disease. HIV Med 2008; 9(Suppl. 1):5 (abstract no. O16).

New-fill used to treat lipoatropy in feet

Fat loss (lipoatrophy) has been widely reported from the face, arms, legs and buttocks. Swtiching from d4T or AZT to either abacavir or tenofovir can lead to slow return of fat in the arms and legs but not in the face. Facial fat loss can be corrected by New-Fill. No treatments has been researched or approved for loss of buttock fat.

The lipoatrophy clinic at the Chelsea and Westminster Hospital has already used polylactic acid (New-fill, Scultptra) treated hundreds of patients on the NHS to correct facial fat loss.

A poster at BHIVA reported the use of New-fill to help seven people who had also lost fat from the soles of their feet. Fat loss was significant enough to make walking painful and difficult, which New-fill helped by generating a cushion of new collagen growth. Each patient received three courses of injections, each two weeks apart.

Patient assessed impact on pain, distress and mobility significantly improved at week 8 (p=0.002). Skin and sub-cutaneous tissue thickness significantly increased by the same time point (p=0.005 and p=0.04, respectively).

This is the first time New-fill treatment for metatarsal fat pad lipoatrophy has been reported and is an example of leading UK clinical practice.

Ref: Kavouni A et al. Treatment of metatarsal fat pad lipoatrophy with volumising injections. HIV Med 2008; 9(Suppl. 1):35 (abstract no. P94).

Use of fibroscan as non-invasive alternative to liver biopsy in HCV/HIV coinfection

Rodger and colleagues from the Royal Free presented results from the use of FirboScan in 30 HIV-positive patients with chronic liver disease related to HBV, HCV, alcohol and steotosis.

Liver fibrosis was evaluated using the METAVIR scoring system. Fibroscan measures of <7.9 Kpa were used as the cut off for no or minimal fibrosis (F0/1) and >11.9Kpa as the cut off for severe fibrosis (F4).

Twelve patients had liver biopsy scores of F0/1 and 16 had scores of F3/4.

Stiffness was significantly correlated to stage of fibrosis (r=0.68, P<0.0001). Median values for F0/F1 were 5.6 Kpa (range 3.6–10.2) and for F4, 14.3 Kpa (range 7.8–67.9). Patients with cirrhosis (F4) were detected with a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 91%. For moderate or severe fibrosis (>F2) a cut off of >7.9 Kpa gave a PPV of 92% and a NPV of 76%. Minimal fibrosis (F0/F1) was detected with a PPV of 61% and a NPV of 92%.

The authors concluded that FibroScan is a reliable method for the diagnosis of significant fibrosis (>F2) and cirrhosis (F4) in HIV-positive patients with chronic liver disease, although further research is needed to inform its use in monitoring over time.

Ref: Rodger A et al. Assessment of staging of liver fibrosis by transient elastography in HIV-positive patients with chronic liver disease using liver biopsy as the gold standard. HIV Med 2008; 9(Suppl. 1):29 (abstract no. P72).

Choice of ARVs for people after organ transplantation

A poster from Kings College and St Thomas presented three case studies of ARV drug interactions with immunosuppressents in transplant recipients, that resulted in significant toxicity and treatment changes.

Case 1 was a 56 year old woman who underwent liver transplantation for hepatitis B who subsequently acquired HIV. After starting saquinavir/ritonavir based HAART (1000/100mg BID), her previously stable ciclosporin levels (normal range <200 mcg/L) peaked at 1005 mcg/L, requiring hospital admission for renal function. This required reducing the ciclosporin dose to 25 mg every third day.

Case 2 was a 37 year old HIV positive man on stable tacrolimus based immunosuppression following a hepatitis B-related liver transplant. When efavirenz was switched to nevirapine tacrolimus levels increased, peaking at 22 mcg/mL (normal range 1–12 mcg/L) and with worsening renal function.

Case 3 was a 40 year old HIV positive man underwent renal transplantation for HIVAN. His HAART regimen included fosamprenavir/ritonavir (700/100 mg BD). On starting cyclosporin, his fosamprenavir levels increased to 4000 ng/mL (therapeutic range <400 ng/mL) associated with disabling diarrhoea requiring discontinuation of ritonavir.

The researchers noted the importance of an awareness on the potential interaction between protease inhibitors and immunesuppressing treatment, and suggested “that patients with RTI options should also consider raltegravir and T-20 during the peri-transplant period because of their minimal interactions with cytochrome P450 and P-glycoprotein”.

Ref: Nathan B at al. Interactions between immunosuppressants and antiretroviral therapy (ARVT) in solid organ transplant recipients: a role for non-nucleoside reverse transcriptase and protease inhibitor-sparing regimes. HIV Med 2008; 9(Suppl. 1):43 (abstract no. P124).

Cases of ventricular tachycardia and atazanavir/r and methadone

Keiran and colleagues presented three cases of tachyarrythmia in patients on atazanavir/r-based HAART, who were also being prescribed methadone (which in vitro has been shown to prolong the QT interval).

Case 1 was a 47-year-old IDU who presented post syncope with prolonged QTc of 539 ms. Telemetry showed episodes of Ventricular Tachycardia (VT). His medications included ATV/r, tenofovir. FTC, methadone 120 mL, nitrazepam 30 mg and diazepam 10 mg tds. When HAART and benzodiazepines were stopped, QTc reduced to 512 ms.

Case 2: A 37-year-old IDU presented post collapse. ECG revealed VT. He underwent emergency cardioversion. QTc post cardioversion was 541 ms. He was prescribed ATVr, abacavir, 3TC, methadone 80 mL and diazepam 10 mg three times a day. 12 nitrazepam 30 mg tablets had been taken. When HAART was stopped, QTc reduced to 431 ms.

Case 3 was 35-year-old IDU presented post syncope with a torsade de pointes arrythmia. His QTc was 712. He had He was receiving ATVr, FTC and tenofovir and methadone 110 mL with diazepam 10 mg tds. He had taken 12 nitrazepam 30 mg tablets. When HAART was stopped and the methadone dose was reduced to 90 mL, QTc reduced to 412 ms.

The researchers concluded that “administration of ATVr, methadone and long acting benzodiazepines appears to lengthen the QTc resulting in life threatening tachyarrythmias” and that “further studies are needed to see whether routine ECG monitoring of patients administered ATVr and methadone should be recommended.

Ref: Kieran J et al. Three cases of ventricular tachycardia (VT) in HIV infected intravenous drug users receiving methadone and atazanavir/ritonavir. Poster 92.

Lower bilirubin increases in HCV-positive patients using atazanavir

A retrospective case note review of patients using atazanavir-based HAART reported in a multivariate analysis, an unexpected ‘protective effect’ on lower bilirubin levels from HCV coinfection and in patients with a history of injecting drug use (IDU). Changes in bilirubin to week 12, and level at week 12, were the primary and secondary endpoints in the study.

Baseline characteristics of the 79 patients included 58% male, 56% white, 27% black. Mean (+SD) values for age was 35 [+7], CD4 count was 200 [+168] and HIV RNA 4.1 logs [+1.5]. Around 60% were IDU and HCV-positive. The review did not look at results of 14 patients who discontinued atazanavir before week 12.

Mean [SD] bilirubin increase to week 12 was 16 [+16] mmol/L. Factors associated with bigger changes and higher bilirubin at week 12 included baseline ALT, GGT, Alk Phos, methadone use, history of IDU, being white and HCV+. However in multiple regression, only HCV status and history of IDU were independently associated with change in and levels of bilirubin at week 12 (P<0.0001). Increase in bilirubin was lower; 12 [+13] mmol/L for HCV+ versus 21 [+16] for HCV- (p=0.006); and 14 [+17] for IDU versus 21 [+15] mmol/L for no IVDA (p=0.01).

Comment

These finding are limited by small numbers and use of retrospective case notes. It is unclear whether, even if confirmed, this effect is significant enough to have a clinical significance. Ref: Cotter A et al. Patients with HIV and hepatitis C co-infection experience less atazanavir-induced hyperbilirubinaemia. HIV Med 2008; 9(Suppl. 1):22 (abstract no. P45).

2008-05-10
IB080905-06

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