Patrick W. G. Mallon

In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA

BACKGROUNDnNucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described.nnnMETHODSnWe examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks.nnnRESULTSnWe observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues.nnnCONCLUSIONSnIndependent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.

Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia

Acute hepatitis with lactic acidosis is a life-threatening but reversible toxic effect on mitochondria of HIV-1 nucleoside-analogue treatment. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered from nucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptom free patients who receive nucleoside-analogue therapy should have hepatic function constantly monitored, especially those with past or present lactic acidaemia.

Effect of Rosiglitazone on Peroxisome Proliferator-Activated Receptor γ Gene Expression in Human Adipose Tissue Is Limited by Antiretroviral Drug-Induced Mitochondrial Dysfunction

BACKGROUNDnTreatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor gamma (PPARgamma [PPARG gene]). Rosiglitazone (RSG), a PPARgamma agonist, improves congenital lipoatrophy but not HIV lipoatrophy.nnnMETHODSnSerial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied.nnnRESULTSnSubjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid-binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass.nnnCONCLUSIONSnThese data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.

Effect of therapeutic drug monitoring on outcome in antiretroviral experienced HIV-infected individuals

BACKGROUNDnThe role of therapeutic drug monitoring (TDM) in the routine management of HIV-infected individuals is still unclear, largely due to a lack of basic data regarding specific drug concentrations and how they correlate with maximal effect and minimal toxicity within given populations. Nevertheless, it has a potentially important role to play in the management of HIV-infected patients, with the aim of limiting toxicity, optimising antiviral effect and decreasing virological failure and emergence of viral resistance.nnnOBJECTIVESnTo measure serum concentrations of specific antiretroviral drugs in individuals changing antiretroviral therapy and assess relationship to virological response.nnnSTUDY DESIGNnA prospective, non-randomised, 24-week study of 40 antiretroviral experienced HIV-infected patients. Subjects had failed their previous antiretroviral regimen and were beginning new regimens based on genotypic testing. Serum antiretroviral concentrations and virological response was measured after initiation of treatment.nnnRESULTSnThere was a significant correlation between higher concentrations of lopinavir and efavirenz and better virological outcome. This was not seen with amprenavir.nnnCONCLUSIONSnUse of TDM in this setting helps predict virological response to therapy. Optimal use of TDM would require dose adjustment on the basis of a TDM level. Further research is necessary to enable this practice to become routine in the management of HIV-infected patients.

The Safety, Efficacy, and Pharmacokinetic Profile of a Switch in Antiretroviral Therapy to Saquinavir, Ritonavir, and Atazanavir Alone for 48 Weeks and a Switch in the Saquinavir Formulation

BACKGROUNDnToxicities observed with current combination antiretroviral therapy (CART) warrant a search for novel options, such as class-sparing regimens. Ritonavir-boosted double-protease inhibitor (PI)-only regimens are such an option but are prone to pharmacokinetic interactions.nnnMETHODSnThis 48-week randomized study examined the safety and efficacy of a switch in CART to a once-daily regimen of saquinavir (SQV), ritonavir (RTV), and atazanavir (ATV) that did not include nucleoside reverse-transcriptase inhibitors (NRTIs). The study also assessed the pharmacokinetic profile of a change in the SQV formulation, from 200 mg to 500 mg, in 2 regimens (SQV-RTV twice per day plus NRTIs [arm 1] and SQV-RTV-ATV once per day without NRTIs [arm 2]) in human immunodeficiency virus type 1-infected subjects (plasma human immunodeficiency virus RNA level, <50 copies/mL). Patients underwent an initial SQV formulation change or a CART change to SQV-RTV-ATV with intense pharmacokinetic sampling. All patients were subsequently assigned to receive SQV-RTV-ATV (1500, 100, and 300 mg once per day, respectively) without NRTIs for 48 weeks. The primary end point was the percentage of patients who experienced virologic failure.nnnRESULTSnOf 25 subjects enrolled, scleral icterus was the most common adverse event (3 patients [12.5%]). Three subjects (12.5%) experienced virologic failure; and mean (+/- standard error of the mean) increase in the CD4(+) lymphocyte count was 63 +/- 36 cells/ mu L over 48 weeks (P=.012). The SQV geometric mean area under the time curve parameters were not significantly altered for the 2 SQV formulations (arm 1, 23.32 vs. 18.76 ngxh/mL [geometric mean ratio, 0.80] for the 200-mg vs. 500-mg formulations, respectively; arm 2, 50.31 vs. 44.79 ngxh/mL [geometric mean ratio, 0.88], for the 200-mg vs. 500-mg formulations, respectively).nnnCONCLUSIONSnA CART regimen of SQV-RTV-ATV alone demonstrated sustained virologic efficacy and was associated with significant increases in the CD4(+) lymphocyte count.

Evolution of CD4+ T cell count in HIV-1-infected adults receiving antiretroviral therapy with sustained long-term virological suppression.

It is not fully elucidated whether patients who receive antiretroviral therapy (ART) can maintain continued CD4 count increases. Previous studies suggested a plateau 2-4 years after treatment initiation. We aimed to characterize the evolution of CD4 counts in HIV-infected individuals receiving long-term suppressive ART, by performing a retrospective study of patients who maintained viral suppression (HIV RNA <400 copies/ml) for > or =5 years. We used linear regression models to determine for each individual whether the CD4 count continued to increase or plateau. Furthermore, we estimated whether the slope of the CD4 count for each individual became zero, which we defined as the CD4 set-point. We assessed factors associated with continued CD4 count rise, reaching a CD4 set-point and time to the CD4 set-point. Fifty-nine patients were included. The median baseline CD4 count was 238 (IQR, 120-360) cells/microl and the median duration on ART was 7.6 (IQR, 5.9-9.3) years. On ART, CD4 count continued to increase in 37 subjects (63%). Significant predictors of continued CD4 count increase included a lower baseline log10 HIV RNA (OR, 0.35; 95% CI, 0.14-0.89; p=0.026) and a shorter duration on ART (OR, 0.65; 95% CI, 0.47-0.91; p=0.021). Twenty-four (41%) subjects reached a set-point after a median 4.3 (IQR 1.8-6.4) years on ART. A lower baseline CD4 percentage was associated with both a longer time to reach the CD4 set-point and a lower CD4 count at the CD4 set-point. These findings suggest that CD4 count may continue to increase in some patients after several years of ART. Our results point to an advantage to commencing ART at higher CD4+ T cell strata. These data should be considered when estimating the optimal time to initiate ART.

Something moving in my head

A 52-year-old woman of Caribbean origin, who had lived in the UK for 30 years, presented in December, 1998, 2 days after a 3-week visit to Trinidad, with fever, malaise, and painful scalp ulcers. Whilst away she had received numerous insect bites whose sites had recently become red and painful. This coincided with fevers, rigors, general malaise, and a throbbing pain over the back of her head in which holes developed. She had been previously well and took no medication. She had made annual visits to Trinidad for several years. Her eight travel companions were well. She was feverish (38·3oC); there were three small deep ulcers on the back of her head; the largest measured 2 cm 2 cm 1 cm deep, the others 1 c m 1 c m 1 cm. All had black necrotic centres (figure). The overlying skin was erythematous, warm, and tender in an area extending from occiput to vertex. Except for this, and multiple inflamed bite marks on the arms and legs, physical examination was normal. Intravenous benzylpenicillin (1·2 g 6-hourly), flucloxacillin (1 gm 6hourly), and metronidazole (500 mg 8-hourly) were started. Haemoglobin was 12·9 gm/dL, platelets 3 8 5 1 0/L, and white cells 26·7 1 0/L, with 79% neutrophils. C-reactive-protein was 306·4 mg/L. Liver and renal function tests were normal. A skull radiograph showed no evidence of osteomyelitis. A group A haemolytic Streptococcus was isolated from blood cultures, scalp ulcers, and bite sites.

Chapter 33 – Toxicities of Antiretroviral Therapy

This chapter discusses the issues of toxicity, concentrating on HIV-associated lipodystrophy (HIVLD). In addition to the prevalence of specific side effects and risk factors associated with their development, possible pathogenic mechanisms behind the abnormalities are also discussed. With considerable research into the etiology and pathogenesis of HIVLD continuing, the mechanisms behind the syndrome are starting to unravel. With increased understanding of fat metabolism, this research has helped one to realize the important role of adipose tissue function, not only in the setting of HIV infection, with essential roles for fat in many of the bodys functions such as lipid and glucose homeostasis. The chapter also provides an insight into current and future management strategies to cope with these problems. Management of hepatotoxicity in the setting of HIV-infection should include vaccination against viral hepatitis, preventive strategies to avoid exposure to HCV, treatment of concurrent viral hepatitis, careful monitoring of liver function tests while receiving antiretroviral therapy, and cessation of suspected agents in cases of derangement of liver function.