Clinical update: adverse eﬀ ects of antiretroviral therapy
See New Drug Class page 81
The adverse eﬀ ects of antiretroviral therapy (ART) cause history, lipoatrophy and fat accumulation (and the ARTs substantial morbidity and compromise adherence, which
that cause them), metabolic syndrome, and hepatitis C
can lead to drug resistance. Treatment guidelines recom-
infection.8 Stavudine, indinavir, ritonavir (even at the
mend against universal immediate ART, partly because of
low boosting dose) and lopinavir, but not atazanavir or
See Online for webtable
toxicities (table). The webtable lists licensed ARTs.
amprenavir, induce insulin resistance acutely, but long-
HIV lipodystrophy is characterised by peripheral sub-
term eﬀ ects are unknown. Fasting blood glucose is a
cutaneous lipoatrophy, relative central fat accumulation,
poor measure of insulin resistance and diagnoses less
lipomatosis, dyslipidaemia, insulin resistance, and hyper-
than half of all diabetes in HIV-infected adults. When
lactataemia. Over the ﬁ rst 6 months of ART, limb and other cardiovascular risks factors are present, an oral visceral fat increase, often followed by a progressive and
glucose tolerance test should be considered. Metformin
selective loss of limb fat.1 Zidovudine and stavudine are
improves insulin sensitivity and systolic blood pressure,
the drugs most associated with lipoatrophy. About 30%
and may reduce visceral fat. Thiazolinediones also
of patients receiving stavudine for 2 years developed improve insulin sensitivity; rosiglitazone, but not pio-lipoatrophy compared with 6% of tenofovir recipients.2
glitazone, aggravates dyslipidaemia.
Abacavir, emtricitabine, lamivudine, and tenofovir do
A large prospective cohort study reported a 16%
not seem to induce much lipoatrophy; the protease relative increase in the incidence of myocardial in-inhibitor nelﬁ navir accelerated lipoatrophy, but another
farc tion per year of ART exposure, an eﬀ ect mainly
such drug, lopinavir, might prevent it.3 Lipoatrophy associated with the duration of protease inhibitor can be largely prevented by avoidance of stavudine therapy.9 About half of this association was explained and zidovudine. Switching stavudine or zidovudine by hypercholesterolaemia, hypertriglyceridaemia, and to tenofovir or abacavir improves lipoatrophy, but low HDL-cholesterol. Nevertheless, traditional risk normalisation can take years.4 Cessation of protease factors (older age, being male, smoking, hypertension, inhibitor therapy may improve visceral adiposity.
diabetes, pre-ART dyslipidaemia) are collectively more
Thiazolidinediones have a small or no eﬀ ect on HIV important than ART. The overall cardiovascular risk
lipoatrophy.5 Uridine and pravastatin may improve associated with ART is declining, possibly because of lipoatrophy more rapidly and substantially than the increasing use of lipid-lowering drugs, less smoking, zidovudine or stavudine switching.6,7 Cosmetic inter-
and use of more lipid-neutral ART.9 Surprisingly,
ventions, such as poly-L-lactic acid injec tions, modestly however, intermittent ART modestly increased rather improve facial lipoatrophy. Growth hor
mone and a than decreased the cardio vascular event rate compared
growth-hormone releasing-hormone analogue improve
with continuous ART. This increase may relate to the
visceral abdominal fat accumulation, but aggravate observed slight increase in the ratio of total cholesterol lipo atrophy and, at least for growth hormone, insulin to HDL-cholesterol with intermittent ART.10resistance and dyslipidaemia.1 Met formin also improves
All cardiovascular risk factors should be assessed before
visceral adiposity, but the eﬀ ect is modest.
starting ART and about annually thereafter. Cessation
Most protease inhibitors (except unboosted ata-
of smoking is likely to be the single most eﬀ ective
zanavir, but including low-dose ritonavir), efavirenz, intervention. Intensive diet and exercise over 6 months stav
udine, and zidovudine increase total cholesterol, improved central obesity and systolic blood pressure in
LDL-cholesterol, and triglyceride concentrations.1 The HIV-infected adults with metabolic syndrome, but lipid change in risk of cardiovascular disease with ART (esti-
mated by the Framingham equation) is generally not
For hypercholesterolaemia, pravastatin is most used
substantial unless other cardiovascular risk factors are because its metabolism is unaﬀ ected by ART, although present, perhaps partly because most potent ART also its eﬀ ects may be less than in HIV-uninfected adults. increases HDL-cholesterol concentrations.
Plasma concentrations of more potent statins, such
Diabetes mellitus occurs in 6–10% of those receiving as rosuvastatin and atorvastatin, can be increased by
ART. Risk factors include increasing age, obesity, family protease inhibitors, which increases the risk of statin
www.thelancet.comVol 370 July 7, 2007
toxicity. If used, these statins should be started at lower
Side-eﬀ ect New learning points Most promising therapies*
than normal doses. Ezetimide is also eﬀ ective at lowering
LDL-cholesterol. The other option for dyslipidaemia is to
switch boosted protease inhibitors, efavirenz, and/or
Contribution of protease inhibitors less
some nucleoside analogues to other virologically active
lipid-neutral ART. Because ART is generally given long-
stavudine, zidovudine, or protease inhibitor
Treatment directions limited by uncertainty
term, switching is an attractive option because it avoids
about whether central fat accumulation is
permanently treating drug toxicity with another drug.
direct drug eﬀ ect or secondary to lipoatrophy analogue
Mechanisms of hepatotoxicity include direct anti-
Protease inhibitor and/or tNRTI cessation
retroviral toxicity, hypersensitivity, immune recon-
Pravastatin, low-dose atorvastatin, or rosuvastatin
stitution in those with chronic viral hepatitis, and
Fasting glucose is poor tool for diagnosis of
hepatitis secondary to mitochondrial toxicity
caused by nucleoside reverse-transcriptase inhibitors.
Consider oral glucose tolerance testing in higher-risk patients
Liver toxicity is generally more frequent in patients
Withdrawal of ART increases risk, perhaps
Address all risk factors, such as smoking,
with chronic viral hepatitis or increased baseline hepatic
Traditional risk factors aﬀ ect risk more
aminotransferases and in people who abuse alcohol.
5% of nevirapine-exposed patients develop hepatitis in
Nevirapine be initiated only in ART-naive
the ﬁ rst 3 months of therapy, and in half of these a rash
counts <400 and 250 cells per µL, respectively
also occurs. Because immunocompetence is a signiﬁ cant
Didanosine associated rarely with hepatic ﬁ brosis, nodular regenerative hyperplasia,
risk factor, guidelines recommend that nevirapine be
started only in ART-naive men and women with CD4+
Abacavir hypersensitivity strongly linked to
lymphocyte counts less than 400 and 250 cells per µL,
Tenofovir associated with small increased
respectively.12 Patients already receiving ART who switch
risk of osteopenia over 3 years, but not with
to nevirapine above these CD4 thresholds may not have
increased fracture rateRole of routine screening (bone mineral
this greater risk of hepatitis.13 Idiopathic hepatic ﬁ brosis
was found in 2% of HIV-infected adults and was related
Tenofovir associated with small increased
to cumulative didanosine exposure. Moreover, long-
Maybe less severe with use of needle-free
term didanosine therapy is rarely linked to nodular
Has substantially aﬀ ected use of enfuvirtide
Tenofovir can induce nephrotoxicity. In two phase III
DEXA=dual-energy X-ray absorptiometry. tNRTI=thymidine nucleoside reverse-transcriptase inhibitor. *In addition to drug withdrawal and avoidance in higher-risk patients.
trials, no tenofovir-induced grade 3 or 4 nephrotoxicity (estimated glomerular ﬁ ltration rate [eGFR] less than
Table: Recent advances in understanding of antiretroviral toxicity
50 mL per min per 1·73 m²) was observed, although eGFR fell by a mean 10%.15 In cohorts, however, about in black Americans and Africans. Deaths have occurred 4% of tenofovir recipients had decreased creatinine clear-
after unsupervised rechallenge, which is contraindicated.
ance of more than 50% after a median 12 months, a rate Adults with the HLA-B*5701 haplotype are at very high about 60% greater than that without tenofovir.16 Risk risk of abacavir hypersensitivity. Molecular screening factors for this signiﬁ cant GFR decline were a low CD4+ for HLA-B*5701 has positive and negative predictive count, hypertension, anaemia, impaired renal function, values of about 80% and 96%, respectively. Screening injection drug use, diabetes, and the use of a boosted decreased hypersensitivity from 9% to 2%, and lowered protease inhibitor, which increases tenofovir levels by the cessation rate in those with uncertain symptoms.17about 30%. Consensus guidelines recommend that eGFR
HIV-infected adults receiving ART have more osteo-
be estimated before ART and at least every 6 months in penia than uninfected adults. The relative contributions those receiving tenofovir.
of ART, HIV, and patients’ characteristics are unknown.
Abacavir causes a hypersensitivity reaction, including Tenofovir is associated with signiﬁ cantly more osteo-
fever, rash, fatigue, and gastrointestinal symptoms after penia than stavudine. No study has been large enough to a mean 10 days in 8% of unselected white adults, but less
assess whether the low bone-mineral density (BMD) will
www.thelancet.comVol 370 July 7, 2007
translate into an increased fracture rate. Measurement A Calmy declares that she has no conﬂ ict of interest. BH has received travel of BMD should be considered in high-risk patients. grants and speakers’ honoraria from Abbott, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Merck Sharp & Dohme, and Roche. DAC has received
Alendronate for 48 weeks signiﬁ cantly increased BMD advisory and consultancy fees, honoraria, and grant support from
GlaxoSmithKline, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Abbott,
Boehringer Ingelheim, Johnson & Johnson, and Gilead Sciences. A Carr has
There are some important diﬀ erences in the pattern of received research grants or funding from Abbott and Roche; consultancy fees
from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, and GlaxoSmithKline;
toxicity in resource-poor settings, in which most patients and lecture sponsorships from Abbott, Boehringer-Ingelheim, Bristol-Myers start ART with nevirapine, lamivudine, and either stavu-
Squibb, Gilead, and GlaxoSmithKline; and has served on advisory boards for Abbott and Roche.
dine or zidovudine. Because of the few altern
atives, 1 Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in
patients often endure chronic toxicity to receive the bene-
HIV-infected adults. N Engl J Med 2005; 352: 48–62.
ﬁ ts of ART. A South African study showed a 1·5% annual 2
Law M, Puls R, Cheng AK, Cooper DA, Carr A. Evaluation of the HIV lipodystrophy case deﬁ nition in a placebo-controlled, 144-week trial in
risk of symptomatic hyperlactataemia with stavudine
antiretroviral-naive adults. Antivir Ther 2006; 11: 179–86.
(al though rechallenge with zidovudine in some patients 3
Haubrich R, Riddler S, DiRienzo G, et al. Metabolic outcomes of ACTG 5142. 14th CROI, 2007: 38 (abstr).
was reported as safe).18 Risk of nevirapine rash was 4 Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of 2·8 times higher in Thai adults than white adults.19 In Africa,
tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006; 20: 2043–50.
grade 2–4 anae mia occurred in 12% of adults, compared 5
Slama L, Lanoy E, Valentin MA, et al. Eﬀ ect of pioglitazone on HIV-1 related lipoatrophy. 13th CROI, 2006: 151LB (abstr).
with 2% in Europe and the USA.20 Low CD4+ count, female 6 Sutinen J, Walker UA, Sevastianova K, et al. Uridine supplementation sex, anaemia, low body-mass index, and being ART-naive
increases subcutaneous fat in patients with HAART-associated lipodystrophy (HAL). 7th Int Workshop on Adverse Events and
were the main risk factors. Issues of toxicity led WHO to
Lipodystrophy in HIV, 2005: 7 (abstr).
change its ART guidelines in 2006 and exclude stavudine 7
Mallon PW, Miller J, Kovacic JC, et al. Eﬀ ect of pravastatin on body composition and markers of cardiovascular disease in HIV-infected men.
from ﬁ rst-line ART. If used, the recommended dose of
AIDS 2006; 20: 1003–10.
stavudine is now 30 mg twice daily, regardless of weight.
Brar I, Shuter J, Thomas A, Daniels E, Absalon J. A comparison of factors associated with prevalent diabetes mellitus among HIV-infected,
10–25% of patients starting ART develop an immune
antiretroviral-naive individuals versus individuals in the National Health and Nutritional Examination Survey Cohort.
reconstitution inﬂ ammatory syndrome: fever, a constitu-
J Acquir Immune Deﬁ c Syndr 2007; 45: 66–71.
tional illness, and inﬂ ammation at the site of previously 9 DAD Study Group. Class of antiretroviral drugs and the risk of myocardial
infarction. N Engl J Med 2007; 356: 1723–35.
unrecognised replication of an opportunistic pathogen, 10 Phillips A, Carr A, Neuhaus J, et al. Interruption of ART and risk of such as Mycobacterium tuberculosis. This illness is more
cardiovascular disease: ﬁ ndings from SMART. 14th CROI, 2007: 41 (abstr).
11 Fitch KV, Anderson EJ, Hubbard JL, et al. Eﬀ ects of a lifestyle modiﬁ cation
common in patients with advanced immunosuppression.
program in HIV-infected patients with the metabolic syndrome.
The syndrome is not a drug-speciﬁ c side-eﬀ ect, rather a
AIDS 2006; 20: 1843–50.
12 DHSS. Guidelines for the use of antiretroviral agents in HIV-1-infected
consequence of rapidly improving immune function.
adults and adolescents. Oct 10, 2006. http://aidsinfo.nih.gov/contentﬁ les/AdultandAdolescentGL.pdf (accessed May 5, 2007).
More potential toxicities are now studied preclinically, 13 Mocroft A, Staszewski S, Weber R, et al. Risk of discontinuation of
in particular mitochondrial toxicity. Several drugs have
nevirapine due to toxicities in antiretroviral-naive and experienced patients with high and low CD4 counts. XVI Int AIDS Conf, 2006: THAB0104 (abstr).
been or will soon be withdrawn from the market, in part 14 Mallet V, Blanchard P, Verkarre V, et al. Nodular regenerative hyperlpasia is for toxicity: soft-gel saquinavir (diarrhoea, nausea), zalcita-
a new cause of chronic liver disease in HIV-infected patients. AIDS 2007; 21: 187–92.
bine (peripheral neuropathy), and extended-release stavu-
15 Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and
dine (pancreatitis, lipoatrophy, and periph
efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251–60.
neuro pathy). A continuing issue for a disease requiring life-
16 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function
long therapy is the short duration of registra tional ran dom-
associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;
ised trials, usually no more than 2 years. There is a need for
17 Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases
the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006; 43: 99–102.
18 Osler M, Stead D, Rebe K, Boulle A, Meintjes G. Severe hyperlactatemia
*Alexandra Calmy, Bernard Hirschel, David A Cooper,
complicating ART with stavudine ﬁ rst-line therapy in South Africa:
incidence, risk factors, and outcomes. 14th CROI, 2007: 792 (abstr).
19 Kappelhoﬀ BS, van Leth F, Robinson PA, et al. Are adverse events of
St Vincent’s Hospital, Sydney 2010, NSW, Australia (A Calmy, DAC,
nevirapine and efavirenz related to plasma concentrations? Antivir Ther
A Carr); Service des Maladies Infectieuses, Hôpital Cantonal
2005; 10: 489–98.
Universitaire de Genève, Geneva, Switzerland (A Calmy, BH); and
20 Ssali F, Stohr W, Munderi P, et al. Prevalence, incidence and predictors of
severe anaemia with zidovudine-containing regimens in African adults
National Centre in HIV Epidemiology and Clinical Research,
with HIV infection within the DART trial. Antivir Ther 2006; 11: 741–49.
University of New South Wales, Sydney, NSW, Australia (DAC)firstname.lastname@example.org
www.thelancet.comVol 370 July 7, 2007
Conformation of therapeutic lens, from bacterial cellulose with ciprofloxacin incorporation for medical application C. M. Caliri1, R. Marchetto1, W. R. Lustri,Y. Messaddeq. 1Instituto de Química – UNESP, Araraquara, SP, Brazil Currently, several methods have been proposed for the controlled release of ophthalmic drugs using soft contact lenses. However, the current systems do not p
DVD's disponíveis no CENTRO DE DOCUMENTAÇÃO PORTUGAL O Poço - espectáculo interactivo para criançasLove Series not talking about perfection / Love series ritual of love and deathUma Bailarina na Escola (vídeo promocional)Valentim e Valentina (versão Guimarães)Projecto "Respira" (registo de imagem)"És tu Zé? + Valsa Lenta" de José Laginha / "Polo non hav