Approaches to the management of antiretroviral toxicity

Frederick J. Lee: Department of Clinical Immunology, Royal Prince Alfred Hospital and The University of Sydney NSW

With no method currently available for achieving sustained virological remission, life-long combination antiretroviral therapy (cART) remains the standard of care for human immunodeficiency virus (HIV) infection. As such, minimisation of treatment toxicity remains a priority for HIV physicians, particularly as acquired immune deficiency syndrome (AIDS) events have declined, leaving non-AIDS events as the major cause of morbidity and mortality. Although progressive refinements in antiretroviral formulations and new drug classes have altered the profile of cART-related adverse events over the past two decades – at least in resource-rich settings – multiple lines of evidence continue to point to antiretroviral drugs as a contributing factor in cardiovascular disease, renal impairment and metabolic bone abnormalities.

This section examines the evidence for toxicities associated with cART and clinical approaches to their management, with an emphasis upon antiretroviral drugs in current usage.

Cardiovascular risk and disease

In Australia, cardiovascular disease is a leading cause of morbidity and mortality among people with HIV infection; coronary artery disease has an incidence in HIV-positive cohorts approximately twice that of the general population – even when matched for age, gender and traditional risk factors (e.g. smoking, hypertension, family history).[1] In the setting of HIV infection, cardiovascular disease may have a complex, multifactorial pathogenesis, with direct viral effects, inflammation from chronic immune stimulation, antiretroviral drug effects, and traditional risk factors all proposed as contributing factors, although in vivo evidence of these mechanisms is limited. Lipodystrophy and insulin resistance are no longer prominent as adverse events with the current generation of antiretroviral drugs, but associations with dyslipidaemia and risk of myocardial infarction remain.

Dyslipidaemia and combination antiretroviral therapy

The requirement for combination therapy means it is not possible to define any single fasting lipid profile as representative of cART-associated dyslipidaemia. Rather, the different classes, and in some cases individual drugs need to be considered separately. Fasting lipid effects, categorised by antiretroviral class, are presented in Table 1.

Table 1. Effects of antiretroviral drugs on fasting lipids
Antiretroviral agent Fasting lipid effects
Total cholesterol

LDL

cholesterol

HDL cholesterol Triglycerides
Nucleos(t)ide reverse transcriptase inhibitors (NRTIs)
abacavir [2][3] ­ ­ ­
didanosine [4] ­­ ­­ ­
emtricitabine or lamivudine Effects unclear – confounded by coformulations with other NRTI drugs
stavudine [5] ­­ ­­ ­­
tenofovir [6] ­ ­
zidovudine [7] ­ ­ ­ ­
Non-nucleoside reverse transcriptase inhibitors
efavirenz [8] ­­ ­ ­ ­
etravirine [9] ­
nevirapine [10] ­­ ­­ ­­ ¯
rilpivirine [11] No significant lipid effect reported
Protease inhibitors*
atazanavir [12][13] –/­ –/­ –/­
darunavir [14] ­­ ­ ­ ­
fosamprenavir [15] ­­ ­­ ­­
indinavir [16] ­­ ­­ ­­
lopinavir [17] ­­ ­­ ­
nelfinavir [18] ­ ­ ­
ritonavir (full-dose) [19] ­­ ­­ ­­
saquinavir [20] ­ ­ ­­
tipranavir [21] ­ ­ ­
Pharmacokinetic boosters of protease inhibitors
low-dose ritonavir [22][23] –/­ –/­ –/¯ –/­
cobicistat [24] –/­
Integrase strand transfer inhibitors, CCR5 receptor antagonists, entry inhibitors No significant lipid effect reported to date [25][26][27][28]
* Lipid effects of protease inhibitors are for ritonavir-boosted forms, excepting nelfinavir
† Either 100 mg daily or twice daily. Fasting lipid effects dose-dependent; magnified with the higher daily dose
‡Cobicistat 150 mg daily has similar, non-significant fasting lipid effects to ritonavir 100 mg daily
HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Protease inhibitors (PIs) – with or without ritonavir boosting – have historically been most strongly associated with dyslipidaemia; increases in total, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol and triglycerides were reported in 38-70% of patients treated with early generation (unboosted) PIs (indinavir, saquinavir), with minimal effect upon high-density lipoprotein (HDL) cholesterol levels.[29][30] This change is evident after only 4 weeks of treatment, and is maintained at 48 weeks. However, by comparison, the current generation (boosted) PIs – atazanavir/ritonavir and once-daily darunavir/ritonavir – both have a favourable fasting lipid profile (lower total and non-HDL cholesterol fractions, lower triglycerides).[31] Switching away from ritonavir-boosted PIs improves the lipid profile, suggesting at least a partial reversibility. This has been applied to clinical practice in several studies, positioning it as a feasible treatment option for dyslipidaemia in patients receiving a ritonavir-boosted PI.[32][33] At the time of writing, a fixed-dose combination of atazanavir/cobicistat has been approved, and another fixed-dose combination (darunavir/cobicistat with tenofovir alafenamide and emtricitabine) is in phase 3 of clinical trials. The removal of low-dose ritonavir may improve the lipid profile, although in randomised studies comparing atazanavir/ritonavir to atazanavir/cobicistat, the difference in changes to total fasting cholesterol was non-significant.[34]

Of the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz, until recently one of the recommended anchor drugs for initial cART, and nevirapine, both lead to absolute increases in total cholesterol and triglyceride changes similar to that seen with the boosted PI lopinavir/ritonavir.[35] However, whereas lopinavir/ritonavir is associated with an increased risk of myocardial infarction, neither of these NNRTIs are. This discrepancy may be the result of pro-atherogenic increases in total and LDL cholesterol being offset by increases in HDL cholesterol (particularly with nevirapine), as well as PIs contributing to cardiovascular risk in ways other than dyslipidaemia.[36] Of the two most recently approved NNRTIs, etravirine is associated with a modest elevation in triglycerides,[37] while rilpivirine is not associated with significant lipid effects.

Of the nucleos(t)ide analogue reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate (TDF) and abacavir, each components of all initial cART regimens currently recommended in Australia, appear to produce slight elevations in total, HDL and LDL cholesterol, and triglycerides, but with little change to the total:HDL cholesterol ratio.[38] While a number of studies have shown a statistically significant favourable lipid profile for TDF versus abacavir, the clinical relevance of these differences is unclear.[39][40] Similarly, although TDF has a favourable fasting lipid profile compared to the recently-approved tenofovir alafenamide (TAF) in phase 2 and 3 clinical trials, the changes in total:HDL cholesterol ratio are identical in these two tenofovir prodrugs, potentially limiting the clinical relevance.[41]

Other antiretroviral classes – the viral fusion blocker enfuvirtide, CCR5 receptor antagonists, and integrase strand transfer inhibitors (INSTIs) – all appear to have minimal lipid effects. In particular, the favourable lipid profile of INSTIs, their antiviral potency and good tolerability and safety profiles demonstrated in multiple large randomised controlled trials have seen them become a preferred choice for initial cART in Australia and other resource-rich settings.[42][43]

Myocardial infarction and combination antiretroviral therapy

In 2008, an analysis of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort study reported that recent or current abacavir and didanosine use was associated with a significantly increased risk of myocardial infarction.[44] This increased risk could not be attributed to other risk factors, and it was speculated that abacavir caused a reversible vascular inflammation, with discontinuation returning risk of myocardial infarction to pre-abacavir levels; as yet no convincing biological mechanism has been described to explain this finding.[45]

Following this finding, a number of meta-analyses, including one conducted by the United States Food and Drug Administration (FDA) have failed to replicate the D:A:D abacavir findings (Table 2), although an updated D:A:D analysis showed a persistence of the association with myocardial infarction.[46][47][48] The most recent analysis from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohort study offers a more nuanced interpretation, suggesting that recent abacavir use is associated with myocardial infarction, although the strength of the association declined after adjusting for traditional and HIV-associated risk factors.[49] Thus confusion remains about the role of abacavir in cardiovascular disease. It is worth noting that no prospective randomised study to date has shown an increase in actual event rates, although an extremely large study would be required to demonstrate such a finding. Thus the likelihood of identifying this cardiovascular signal outside of a large cohort study such as D:A:D is low. Abacavir remains a recommended drug in the current United States Department of Health and Human Services (DHHS) guidelines when combined with dolutegravir and lamivudine or emtricitabine, although its use should be avoided in patients with a high baseline cardiac risk.[50]

Table 2. Abacavir and myocardial infarction: available studies
Study Year reported Study type Association
D:A:D[51] 2008 Prospective cohort collaboration Increased risk
SMART[52] 2008

Randomised controlled trial

(post hoc subgroup analysis)

Increased risk
GlaxoSmithKline abacavir study analysis[53] 2009 Industry-sponsored meta-analysis of randomised controlled trials No increased risk
ANRS CO4[54] 2010 Case-control study Equivocal
Danish HIV Cohort[55] 2010 Prospective national cohort Increased risk
ACTG A5001/ALLRT[56] 2011 Investigator-initiated meta-analysis of randomised controlled trials No increased risk
Quebec Public Insurance Database Study[57] 2011 Case-control study Increased risk
Veterans Affairs Clinical Case registry[58] 2011 Retrospective cohort No increased risk
US Food and Drug Administration meta-analysis[59] 2012 Investigator-initiated meta-analysis of randomised controlled trials No increased risk
Swiss HIV Cohort[60] 2015 Retrospective cohort Increased risk
NA-ACCORD[61] 2015 Retrospective cohort Equivocal

The D:A:D study also identified exposure to the PIs indinavir and lopinavir as independent risk factors for myocardial infarction;[62] unlike with abacavir, the effect is cumulative – with a 16% increased risk per year of exposure. No such association has emerged for atazanavir (with or without ritonavir),46 while similar data for darunavir/ritonavir are yet to be reported.

Cardiovascular risk assessment of adults with HIV infection

As people with HIV are subject to the same vascular risk factors as HIV-negative people – frequently more so[63] – these comorbidities should be assessed for and treated before attributing cardiovascular risk to the HIV or to cART (Table 3). A fasting lipid profile (total, HDL, LDL cholesterol, triglycerides) should be obtained before initiating cART, again after starting/switching a cART regimen, and at least once yearly – more frequently if abnormal, or to monitor treatment. Fasting glucose or haemoglobin A1C measurements are both diagnostic tests for diabetes mellitus, and should be examined at entry into care and annually thereafter,[64] with a formal oral glucose tolerance test considered if there is evidence of impaired fasting glucose (≥ 6.1 mmol/L, < 7.0 mmol/L).[65]

Table 3. Secondary causes of dyslipidaemia to consider in PEOPLE WITH HIV-1 infection 
Condition Relevant assessments
Lipodystrophy Use of thymidine analogues (stavudine, zidovudine)
Smoking and alcohol intake Medical history
Diabetes mellitus
  • Regular measurements of fasting glucose
  • Consider oral glucose tolerance testing
  • Glycosylated haemoglobin (HbA1c)
Obesity
  • Body-mass index
  • Waist-to-hip circumference ratio
Hypothyroidism Thyroid function testing
Medications (non antiretroviral)
  • Thiazide diuretics
  • β-blockers
  • Corticosteroids
  • Oral contraceptive pill
  • Atypical anti-psychotics (clozapine, olanzapine)
Hepatic or biliary disease
  • History of excessive alcohol intake
  • Viral hepatitis serology
  • Serum transaminases, bilirubin levels
Chronic kidney disease
  • Proteinuria
  • Elevated serum creatinine
Familial hyperlipidaemia (rare)
  • Known family history
  • Presence of corneal arcus, xanthelasmata and xanthomata

The intensity of intervention should be governed by the overall risk. Multiple algorithms are now available to quantify cardiovascular risk; the Framingham Risk Score, which provides a percentage risk at 10 years, remains the most widely used – and forms the basis of the Australian absolute cardiovascular risk calculator, available as an online tool.

Infectious Diseases Society of America (IDSA) guidelines recommend that the Framingham Risk Score risk assessments be used with National Cholesterol Education Program (NCEP) targets for making assessments of dyslipidaemia in the HIV populace.[66] This guideline assumes that the treatment goals are no different from those of the general population, and while the Framingham Risk Score is a useful tool for conventional risk factors, it likely underestimates the risk for HIV.[67] Alternatives are the D:A:D Estimated Risk Calculator that caters specifically for risk in the population with HIV infection, and the ASCVD risk calculator, which also provides a lifetime risk.

Treatment

Non-pharmacological interventions (smoking cessation, dietary modification, exercise prescription) should be offered to all patients, as these measures alone (if adhered to) may reduce the likelihood of requiring pharmacotherapies. This is particularly true of smoking cessation, which is the modifiable risk factor with the single greatest impact on calculated risk. Individuals with established ischaemic heart disease or risk-equivalent (diabetes mellitus, symptomatic carotid artery disease, abdominal aortic aneurysm, peripheral arterial disease), however, do require concomitant pharmacotherapy. But for people with HIV of lesser cardiovascular risk, it is unclear when pharmacotherapy should be introduced; this will be the focus of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) statin trial.[68]

Although prolonged exposure to cART, particularly to PIs, has been associated with increased arterial stiffness,[69] no clinically relevant association between antiretroviral agents and arterial hypertension has been so far identified. Hypertension should be managed as for the general population, according to the National Heart Foundation of Australia guidelines.[70] These guidelines target a blood pressure of <140/90 mmHg (or lower if tolerated) in the absence of coronary artery disease, a risk-equivalent or chronic kidney disease (CKD). Statins remain the mainstay of pharmacotherapy for hypercholesterolaemia (Figure 1). In patients receiving a PI-based cART regimen, switching to a non-PI-based regimen is an alternative. Both options have their respective pros and cons – switching may successfully remove the underlying cause of hypercholesterolaemia, but exposes the patient to the risk of virological failure, as seen in the SWITCHMRK study.[71] However the boosted PI therapy may not be the cause of hypercholesterolaemia, and statins have proven efficacy in reducing cardiovascular risk.[72] The current European AIDS Clinical Society (EACS) guidelines recommend considering an antiretroviral switch before initiating statin therapy,[73] although the two randomised controlled trials comparing these options have both found statins more effective.[74][75] In the more recent study, there was no difference in absolute risk reduction, however, and the difference between switching and using rosuvastatin was non-significant for current generation boosted PIs (atazanavir/ritonavir, darunavir/ritonavir).

Figure 1. Management of dyslipidaemia in HIV infection * Framingham Risk Score † Equivalent to existing coronary heart disease, other atherosclerotic disease, or diabetes mellitus PI: protease inhibitor

antiretro fig1

Clinicians must exercise caution when initiating statin therapy, because of the potential for drug interactions. This is particularly the case with simvastatin and boosted PIs; atorvastatin and rosuvastatin are less affected by interactions with boosted PIs, but still require a reduced dose. Pravastatin does not require dose adjustment, but in studies of patients with HIV infection, is less effective than either atorvastatin or rosuvastatin.[76]

Renal disease

Renal disease in HIV

HIV infection is an established risk factor for renal pathology; an estimated 5-10% of people with HIV infection in resource-rich settings qualify as having chronic kidney disease – abnormalities of kidney structure or function persisting for 3 or more months.[77] The incidence of acute kidney injury (AKI) is also higher among people with HIV infection.[78] Thus the need for monitoring of renal function and early identification of renal pathology remains an important component of ongoing HIV management.

End-stage renal disease in HIV makes up only 1-3% of serious non-AIDS morbidities.[79] It is however strongly influenced by race, with rates in patients of African descent being eight-fold higher than in Caucasians.[80] No similar data exist for the Indigenous population in Australia, but the already high rate of chronic kidney disease in these peoples suggests a similar degree of disparity is possible.

The classic renal disease in HIV infection is HIV-associated nephropathy, a variant of focal segmental glomerulosclerosis (FSGS) characterised histologically by collapse of the glomerular basement membranes, tubular dilatation, and interstitial inflammation. It is probably mediated by direct effects of the virus upon glomerular epithelial cells. As such, it is seen as a disease of advanced HIV, and seldom seen in the cART era; a diagnosis of HIV-associated nephropathy is regarded as an independent indication to initiate treatment.[81]

As with cardiovascular disease, the common causes of chronic kidney disease in the general population (diabetes mellitus, hypertension, older age) also apply to people with HIV. Additional variables independently associated with greater risk of chronic kidney disease in HIV are: female sex, injecting drug use, higher plasma viral load and lower CD4 lymphocyte count (Table 4).[82] Although the association between cART and improvement over time in renal function or proteinuria has been described, the nephrotoxic potential of specific antiretroviral drugs are also well documented.

Table 4. Variables independently associated with chronic kidney disease in HIV infection IDU: injecting drug use; PI: protease inhibitor; TDF: tenofovir disoproxil fumarate (Adapted with permission from Lucas GM, Ross MJ, Stock PG, et al.)[83]
Variable

Relative risk range of

chronic kidney disease

Relative risk range of

end-stage renal disease

Demographic factors
Age 1.2 – 5.5 per 10 years

2.0 for > 50 years

(vs < 30 years)

African descent 1.7 – 2.4 4.5 – 3.1
Female sex 1.5 – 1.7 Not available
Comorbid medical states
Hypertension 1.4 – 3.5 4.9
Diabetes mellitus 1.5 – 2.6 4.8 – 9.0
Hepatitis C co-infection or IDU 1.3 – 2.2 2.8 – 5.0
HIV-specific factors
HIV RNA plasma viral load

1.3 – 2.2 for detectable

(vs undetectable)

2.0 per log101.0 increase
CD4+ lymphocyte count

1.1 – 1.3 per decline of 0.1 x 109 cells/L

1.4 – 2.2 for <0.2 x 109 cells/L

(vs ≥0.2 x 109 cells/L)

1.7 per decline of 0.1 x 109 cells/L

1.4 – 2.7 for <0.2 x 109 cells/L

(vs ≥0.2 x 109 cells/L)

Antiretroviral drugs
TDF plus a boosted PI 3.4 vs an NNRTI-based regimen without TDF Not available
Indinavir

2.0 – 2.5 for any or recent exposure

(vs no/remote exposure)

Not available
TDF usage

1.2 – 1.3 per year of exposure

1.6 – 2.2 for any/recent exposure

(vs no/remote exposure)

Not available
Atazanavir 1.2 per year of exposure Not available
Lopinavir 1.1 per year of exposure Not available

Renal toxicity and combination antiretroviral therapy

Tenofovir disoproxil fumarate (TDF)

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir, and has received the most attention as a nephrotoxin; it is also the most consistently recommended antiretroviral drug in consensus guidelines, having been a preferred N(t)RTI since 2003.

Structural similarity with the nucleotide analogues adefovir and cidofovir – both known to cause proximal tubulopathy – first raised the possibility of TDF also being nephrotoxic. However, an adverse renal signal was not identified in pre-approval clinical trials. This inability to identify a signal may have been a result of strict inclusion criteria, leading to studies not simulating clinical practice, and it was a year post-approval, in 2002, that the first case reports of TDF-associated generalised proximal tubular dysfunction, or Fanconi syndrome (polyuria, hypophosphataemia, metabolic acidosis, glycosuria, osteomalacia), emerged.[84] TDF-induced renal damage is thought to be a proximal tubular mitochondriopathy, and may also manifest clinically as diabetes insipidus and acute kidney injury.[85]

Evidence of tubular dysfunction may be found in between 17% and 22% of TDF-treated patients,[86] although in most cases there is absence of a decline in the estimated glomerular filtration rate (eGFR). Randomised controlled studies have shown mean declines in eGFR with TDF-containing cART regimens of < 5 mL/min – unlikely to be of clinical relevance.[87] While this is of concern, a standard definition of TDF-associated renal toxicity is lacking, and the difficulty in ascertaining causality for cART-emergent renal dysfunction generates confusion about the true frequency of this phenomenon. Furthermore, the incidence of acute renal failure in randomised studies has been 1% or less, and in a D:A:D analysis with > 200,000 person-years of follow-up, no predictive association was identified between cumulative TDF use and chronic kidney disease.[88] This finding suggests that overt renal failure or chronic kidney disease directly attributable to TDF is in fact quite uncommon, although better awareness of the potential nephrotoxicity of TDF with closer monitoring may have masked a significant and clinically relevant association.

Inhibition of creatinine tubular secretion

The integrase strand transfer inhibitor (INSTI), dolutegravir, causes moderate, non-progressive mean elevations in the serum creatinine of 9 to 18 µmol/L, with accompanying falls in the eGFR by inhibiting the proximal renal tubular cationic transporter OCT2, responsible for the tubular secretion of creatinine.[89] This effect is seen without any deterioration in independently measured glomerular filtration rate. The creatinine rise is acute, typically occurring within 2 weeks of initiation, and plateaus thereafter. The CYP3A isoform inhibitor, cobicistat, used exclusively as a pharmacokinetic booster (at the time of writing, cobicistat is only approved in Australia as a coformulation with elvitegravir, tenofovir and emtricitabine), blocks several proximal tubular transport proteins, resulting in a fall in eGFR similar to that seen with dolutegravir.[90] The NNRTI, rilpivirine, also has an inhibitory effect upon OCT2 and p-glycoprotein.[91] No renal adverse event signal has emerged to date from these drugs, and based upon the available prospective data, the creatinine rise appears to be reversible, at least in the short-to-medium term.

Other antiretroviral drugs

The PIs atazanavir (used with or without ritonavir) and lopinavir/ritonavir have each been identified with an increased risk of chronic kidney disease.[92] Like the early generation PI indinavir, atazanavir may cause nephrolithiasis as well as an interstitial nephritis.

Approach to renal disease in HIV

The major consensus guidelines for management of HIV in resource-rich settings list assessment of renal function at baseline and regular monitoring thereafter as standard of care, using serum biochemistry and urine examinations as screening investigations.[93][94] The Infectious Diseases Society of America (IDSA) guidelines for managing chronic kidney disease in HIV recommend monitoring renal function with creatinine-based eGFR and urine examination when cART is initiated, or the regimen switched, and at least twice-yearly in stable patients. The same estimation method should be used to track trends over time – in Australia the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula is most commonly used to calculate eGFR, as it is considered the most accurate, especially at the higher ranges of filtration rate.[95] The D:A:D CKD Tool  also provides an estimate of GFR. The effect upon antiretroviral prescription will depend upon whether the renal function is normal or abnormal at baseline.

While antiretroviral effect as a cause of cART-emergent renal impairment should always be considered, the background prevalence of chronic kidney disease in the HIV population is between 5-10%,[96] compared to < 5% incidence of cART-associated kidney injury,[97] suggesting that cART is not responsible for most cases of renal impairment. Thus it is inappropriate to respond initially by switching the cART regimen, particularly as it may limit future ART options for a patient if resistant mutants or competing comorbidities emerge. Management should commence, as with other instances of renal impairment, with assessment and exclusion of common comorbidities such as hypertension, diabetes mellitus and non-cART drugs with nephrotoxic potential. However, TDF discontinuation should be considered if the patient experiences a > 25% decline in eGFR from baseline to a level < 60 mL/min that is confirmed with a second measurement.[98]

If it is the baseline renal function which is abnormal, the question shifts to which antiretroviral drugs should be initiated or avoided. IDSA guidelines recommend that TDF not be initiated if the eGFR is < 60 mL/min, but this in turn will be influenced by the need for antiviral efficacy (as HIV is itself a risk factor for renal disease), and if a baseline abnormal renal function could be successfully corrected with other medical therapies, TDF could reasonably be considered. The coformulation of TDF, emtricitabine and elvitegravir/cobicistat should not be initiated in people with an eGFR of < 70 mL/min, as pre-approval trials excluded individuals with eGFRs in this range. However, the same restriction curiously does not apply to regimens containing both dolutegravir and TDF. A 2014 Australian consensus statement on the renal monitoring of patients with HIV infection receiving TDF advocates active monitoring in order to maximise the drug’s ongoing utility as a key component of initial cART using a schedule of regular monitoring with blood and urine testing (Figure 2).[99]

Figure 2. Schematic of suggested renal monitoring when initiating potentially nephrotoxic drugs (Used with permission from: Holt SG, Gracey DM, Levy MT, et al.)[100]

anti retro fig2

The alternative prodrug TAF has similar antiviral efficacy to TDF, but with 90% lower plasma tenofovir concentrations, permissible because TAF is converted to the active form preferentially within lymphocytes. Phase 3 pre-approval studies have demonstrated a statistically significant favourable renal profile for TAF versus TDF – with less decline in eGFR, and lesser urinary excretion of protein, albumin and β2 microglobulin.[101] However, there were no instances of Fanconi syndrome in the study with either TAF or TDF, and whether these differences prove clinically relevant in the medium-to-long term remains to be seen.

Bone disease and combination antiretroviral therapy

Epidemiology

As with cardiovascular and renal disease, people with HIV infection have a higher risk of bone disease than the general population. Observational and cross-sectional study data have identified a significant burden of bone disease, with between 15% and 23% of adults with HIV infection having osteoporosis.[102][103] This represents a four-fold greater prevalence compared to those without HIV.

Epidemiologic data support a direct role for HIV infection in the pathogenesis of bone disease, HIV having been identified as an independent risk factor for reduced bone mineral density (BMD).[104][105] How the virus might directly affect bone mineralisation has not been definitively established, although in vitro the HIV gp120 protein can trigger apoptosis in osteoblasts.[106]

Observations of bone density loss following exposure to cART have been present for more than 10 years, although the mechanism remains unclear. An association between thymidine analogue NRTIs, elevated lactate and reduced bone density has been identified,[107] but these antiretroviral agents are no longer routinely prescribed. Among currently preferred antiretroviral drugs, TDF leads to initial, modest losses over a 6- to 12-month period that plateaus thereafter.[108] TDF may also contribute to osteomalacia as a component of the rare Fanconi syndrome. At least two PIs (indinavir, nelfinavir) have also been shown in vitro to downregulate osteoblastic activity.[109] Clinical data associating PI usage with bone density loss is conflicted, although the most recent study suggests accelerated bone loss with current PIs, compared to raltegravir.[110]

Clinical studies of bone density in cART-treated cohorts are limited by the heterogeneity of treatment regimens, and variability in methods of measuring bone mineral density (BMD). Consequently, it is difficult to infer the clinical relevance of reported BMD changes attributed to cART in terms of absolute fracture risk, or to actual rates of fracture. A retrospective analysis of the large United States Veterans Health Administration registry found an association between established risk factors (age, race, low body-mass index, smoking) and increased fracture rate, but not with cumulative cART use, in 46,062 person-years of follow-up.[111] Thus far the effect of cART on the actual osteoporotic fracture rate has not been prospectively evaluated.

Assessment and management

Assessments specific for metabolic bone disease are not routinely performed at entry into care for HIV, although the history and other baseline investigations may reveal established risk factors for future fractures – smoking and alcohol consumption, past fragility fracture(s) and falls, poor nutrition, exposure to corticosteroids, signs of hypogonadism and renal impairment. These risk factors should be identified and addressed.

EACS management guidelines favour a dual-energy X-ray absorptiometry (DXA) scan-based approach to diagnosis of bone disease and risk stratification, with scanning recommended before cART initiation for: post-menopausal women and men aged 50 years or over; individuals with a history of minimal trauma fracture or at high risk of falls, clinical hypogonadism or systemic corticosteroid use.[112] The Osteo Renal Exchange Program (OREP) differs by preferring to use the Fracture Risk Assessment Tool FRAX® for initial screening in most individuals.[113] The FRAX® algorithm generates a calculated 10-year probability of a major fracture based upon demographic and anthropometric characteristics, and historical risk factors. It can be done either with or without DXA scan data, but country-specific algorithms should be used; one being available for Australia (https://www.shef.ac.uk/FRAX/). It is worth noting that both the EACS and OREP guidelines recommend that HIV infection be regarded as a secondary cause of osteoporosis, although it is not validated as such in the FRAX® algorithm. Clinicians should also be aware that under the Australian Government’s Pharmaceutical Benefits Scheme (PBS), access to anti-resorptive therapy remains tied to the DXA scan result, rather than the fracture risk.

The World Health Organization (WHO) classifications of DXA-based definitions for osteopenia (T-score between -1 and -2.5) and osteoporosis (T-score ≤ -2.5) are the same for people with HIV and the general population. The Z-score, which is a comparison of the BMD relative to an age-matched population, and if abnormal, may provide clues to the existence of secondary causes of osteoporosis (Table 5).

Table 5. Secondary causes of bone density loss to consider
Condition Relevant assessments
Smoking and alcohol intake Medical history
Multiple myeloma
  • Serum and urinary electrophoresis/immunofixation
  • Serum free light chains
Hypogonadism
  • Free testosterone (men)
  • Oestradiol, follicle-stimulating hormone, prolactin (women)
Coeliac disease
  • Anti-deamidated gliadin; anti-tissue transglutaminase
  • Endoscopic small bowel biopsy
Corticosteroid excess
  • Medical history
  • Dexamethasone suppression test
Diabetes mellitus Radial DXA
Hyperparathyroidism Serum biochemistry, parathyroid hormone
Hyperthyroidism Thyroid function testing
Vitamin D deficiency Measurement of 25-OH vitamin D

DXA: dual-energy X-ray absorptiometry.

If osteopenia or osteoporosis is suspected while a person with HIV infection is treatment naïve, selection of an alternative N(t)RTI to TDF, or a ritonavir-boosted PI is preferable. For the more common scenario where a patient develops osteopenia or osteoporosis while established on cART, adequate dietary calcium and vitamin D intake should be prescribed, as well as regular weight-bearing exercise. Antiresorptive therapy such as bisphosphonates may be considered. As no clinical studies have been done in people with HIV for antiresorptive therapies other than alendronate and zoledronic acid, these agents would be considered first-line, although other agents such as teriparatide or the anti-RANKL monoclonal antibody, denosumab, could also be considered.

A number of small studies have already demonstrated that BMD can improve by switching away from PIs to raltegravir,[114] and that switching away from TDF can improve bone turnover markers.[115] Further randomised studies to assess this switch as a treatment option in osteopenic patients with an increased FRAX®-estimated risk score head to head with bisphosphonate therapy are presently underway. Another possible future switch option is TAF, which when compared to TDF, produced a more favourable bone density profile at 48 weeks.

Other adverse events associated with combination antiretroviral therapy

Hypersensitivity reactions

Hypersensitivity reactions primarily manifest as a skin rash, but may also lead to systemic involvement, with fevers, hepatitis and eosinophilia. The differential diagnosis of rashes should include other antimicrobials, especially if the patient is undergoing concomitant treatment for an opportunistic infection. Hypersensitivity may complicate treatment with any antiretroviral drug, but is most commonly associated with NNRTIs. Efavirenz, still probably the most widely-used NNRTI in Australia, causes a rash in 15-27% of patients, but one rarely progressing to systemic involvement.[116] Median time to onset of rash with efavirenz is 11 days, with resolution within 1 month; affected patients can therefore persist with efavirenz, supported by antihistamines and/or corticosteroids as short-term symptomatic therapy, but all rashes should be closely monitored for progression. Rilpivirine, the newest approved NNRTI, has a lower rate of rash than efavirenz.

Nevirapine has the strongest association with hypersensitivity; the reaction is severe in up to 5% of patients, although as a non-preferred antiretroviral agent, its initiation in Australia is now uncommon. Because of the higher risk, nevirapine rash should not be ‘treated through’, as a mild side effect nor should patients be re-challenged to nevirapine.[117] Development of a mild rash without systemic features with nevirapine should not preclude future use of efavirenz.[118] However, other NNRTIs should be avoided if there is a history of toxic epidermal necrolysis or Stevens-Johnson syndrome with nevirapine.[119] If nevirapine is initiated, a 14-day lead-in period at half-dosing (200 mg/day) should be used – this dose escalation strategy decreases the frequency of rash, presumably by autoinduction of nevirapine metabolism.[120]

Abacavir causes a hypersensitivity reaction that includes fever, rash, respiratory and gastrointestinal symptoms after a mean of 10 days in 8% of adults predominantly of European origin (less in persons of African descent), but this risk has been effectively negated by the availability of HLA-B*5701 genotyping,[121] recommended as a standard-of-care test from 2007. Raltegravir has been associated with rare instances of Stevens-Johnson syndrome in post-marketing surveillance, although no causality has been established.

Hepatotoxicity

Treatment-emergent derangements in liver function are one of the most commonly reported laboratory adverse events in randomised trials of initial cART, although clinical sequelae and discontinuation of treatment due to this finding is uncommon, and no signal for chronic liver disease has yet emerged with any antiretroviral class. Initial concerns about hepatotoxicity with maraviroc have not progressed, with no difference seen for severe/high-grade elevations in liver enzymes; this remains under post-marketing surveillance.[122] Clinicians should be mindful however of the potential for immune reactivation leading to a flare of underlying untreated viral hepatitis accompanying immune reactivation following any cART regimen.

Nevirapine is associated with hepatic necrosis at higher CD4 lymphocyte counts, and should not be initiated if the baseline CD4 count is > 0.40 x 109 cells/L in men, or > 0.25 x 109 cells/L in women.[123]

Neuropsychiatric effects

In randomised controlled trials some 53% of patients initiated on efavirenz report neuropsychiatric effects. The symptoms include dizziness, insomnia, abnormal dreams, hallucinations and a sense of dissociation, and may begin as early as the first or second day of therapy. Although the majority of patients develop tolerance to these symptoms after 1 month, between 5% and 9% of patients treated with efavirenz will have persistent and troubling neuropsychiatric symptoms. Studies examining switches away from efavirenz showed that despite significant improvement, there was persistence of neuropsychiatric symptoms, suggesting a component of non-reversibility.[124][125] Dosing prior to sleep may help abate the neuropsychiatric effects, which are the leading cause for premature discontinuation of efavirenz, accounting for much of the superiority of dolutegravir-based regimens in the recent SINGLE trial.[126] Patients should be counselled that mood changes may result with efavirenz, and there may be an increased risk of suicidal ideation;[127] considering the number of alternative antiretroviral agents available, efavirenz use should be re-considered in patients with a history of psychiatric illness.

Myopathy

Raltegravir has been associated with skeletal muscle toxicity, with multiple reports of rhabdomyolysis, and higher rates of elevated serum creatine kinase (CK) in pre-approval studies.[128] The mechanism of this adverse event is unknown; a cross-sectional study comparing raltegravir-based to non-raltegravir-based cART identified a higher prevalence of myalgias and proximal myopathy in the former. But no association was found with duration of raltegravir exposure, or to trough plasma concentration.[129] Caution should be exercised when prescribing raltegravir in patients with concomitant statins or a history of myopathic illness – although it should be noted that in randomised trials, most cases of CK elevation or myalgias were self-limiting, with discontinuation of raltegravir rare. Nor does myopathy appear to be a class effect, with no signal identified for either elvitegravir/cobicistat or for dolutegravir. The NRTI zidovudine may cause myopathy via its mitochondrial effects, but as zidovudine is now uncommonly prescribed in adults, this effect is now rarely seen.

Lipodystrophy

As a vestige of now-superseded antiretroviral therapies, incident cases of HIV lipodystrophy are now very rare. The pathogenesis of HIV lipodystrophy remains unclear, but the strong association with thymidine analogue NRTIs suggests an underlying mitochondriopathy. For affected (and almost universally treatment-experienced) individuals, however, it remains an ongoing management issue, as it is effectively irreversible. If the patient remains on thymidine analogues, switching away from these agents remains the first-line intervention option; this will stop progression. Injection of subcutaneous fillers to affected areas and liposuction are temporary and purely cosmetic, and do not alter the associated metabolic changes. The growth hormone-releasing factor tesamorelin is FDA-approved for the treatment of excess visceral fat in HIV lipodystrophy, but fat rapidly re-accumulates with discontinuation, and long-term safety data are lacking.[130] Metformin and pioglitazone both remain investigational for use in HIV lipodystrophy.

To date, there is no evidence to implicate currently used NRTIs (TDF, abacavir, emtricitabine, lamivudine); nor is there any evidence to completely absolve them as potential causes.

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