Antiretroviral therapy

James McMahon: Alfred Hospital, Monash University, Monash Health and Burnet Institute, Melbourne Vic
Olga Vujovic: Alfred Hospital and Monash University, Melbourne Vic

Historical perspective

The most recent estimate of the global burden of the human immunodeficiency virus (HIV) pandemic published by the Joint United Nations Programme on HIV/AIDS (UNAIDS) in 2015 reported that 36.9 million people are living with HIV/AIDS (PLHIV) and 2 million new infections occurred globally by the end of 2014.[1] Since the introduction of antiretroviral therapy (ART), people living with HIV (PLHIV) have experienced decreasing levels of morbidity and mortality. This declining burden was initially observed in high-income and subsequently in low- to middle-income countries  as ART became more widely available.[2][3] Initial studies of antiretroviral monotherapy reported reductions in levels of circulating HIV with the first clinical trials of the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine in the late 1980s.[4] Despite these initial observations, subsequent elevations in HIV viral load and the selection of drug-resistant strains of HIV[5] were observed in patients receiving monotherapy with this approach failing to extend survival or improve outcomes in the long term.[6][7] These findings lead to the investigation of combination antiretroviral therapy. Randomized clinical trials of different antiretroviral (ARV) combinations reported the virological and clinical superiority of double NRTIs over NRTI monotherapy[8][9] and subsequently the combination of three drugs, including either a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI), over double NRTI regimens.[10][11][12][13]

The advantages of combination ART using three medications as described in these pivotal clinical trials was rapidly translated into reductions in mortality, opportunistic infections and hospital admissions within observational cohorts and routine surveillance systems.[14][15][16] In addition to these early achievements there was also hope that the eradication of HIV might be possible based on findings from viral replication studies and mathematical modelling.[17][18] This early hope of eradication of HIV was discarded with the understanding that latently infected T lymphocytes could archive virus and later re-emerge and propagate after the cessation of ART for much longer periods than originally predicted. The existence of this cellular reservoir prevents the eradication of HIV with currently available ART yet efforts to achieve a sustained remission of HIV off ART have been re-invigorated since the apparent eradication of HIV in the Berlin patient who received a haemopoietic stem-cell transplant to treat leukaemia.[19] Multiple factors may have played a role in achieving a remission in this man including: the repeated myeloablative conditioning and stem cell transplant for relapsed acute myeloid leukaemia, the chronic graft versus host disease post transplant and the fact that the donor stem cells had a homozygous mutation in the CCR5 coreceptor D32 allele, a coreceptor necessary for HIV entry into T cells. This field of research is now the subject of intense basic science research and clinical interventions aimed at the long-term control of HIV without the need for ART.[20]

Because of the success of ART, patients have remained on treatment for longer periods. At the same time there has been increasing recognition of the morbidity  – and in some cases mortality – associated with  short-,  medium-  and  long-term  toxicities  of ART including the HIV lipodystrophy syndrome.[21] It was felt that these toxicities, coupled with the inability to eradicate virus, had to be balanced against the gains from ART when used at CD4 T-lymphocyte (CD4)  cell counts that were protective against opportunistic infections. This approach led to a softening in US guidelines from the Department of Health and Human Services (DHHS) after the year 2000 for asymptomatic individuals with CD4  cell counts above 350 cells/μL where ART was then not recommended, and for CD4 cell counts of 200-350 cells/μL where it should be offered. This advice compares to the previous DHHS recommendation to treat all people with CD4 counts below 500 cells/μL.[22] These recommendations for asymptomatic PLHIV persisted until 2007 in addition to recommendations to treat symptomatic people regardless of CD4 cell count. In 2006 and 2007, the recommendation to initiate therapy in asymptomatic people with CD4 cell counts below 350 cells/ μL was introduced.[23][24]  The rationale for this recommendation in asymptomatic people arose from data gathered from large cohort studies.[25][26][27] These data suggested that starting ART at CD4 cell counts of 350 cells/uL or less would be associated with even better clinical outcomes, especially as concerns over ART-related toxicities were decreasing with the introduction of newer antiretroviral agents in existing and new classes. These findings were supported by randomised clinical trial results that showed that deferring ART to a CD4 cell counts below 200 cells/μL led to increased mortality and incident tuberculosis compared to starting treatment when the CD4 cell counts were between 200 and 350/μL.[28] These recommendations are especially significant for the Australian context because in 2005 the Australian Health Minister's Advisory Committee on HIV and STI endorsed the US DHHS guidelines and requested the Australasian Society for HIV Medicine (ASHM) provide regularly updated commentary on those guidelines relevant to Australia.[29]

In addition to revised recommendations about timing of initiation of ART in asymptomatic people there were also data from observational cohorts and the randomised clinical trial, the Strategies for Management of Antiretroviral Therapy (SMART) study, describing a change in the pattern of morbidity and mortality in PLHIV. While life expectancy has increased due to ART use, these studies report increasing morbidity and mortality from cardiovascular disease, liver cirrhosis and malignancy,[30][31][32] including an association of ART interruption with progression to non- acquired immune deficiency syndrome (AIDS) events.[33][34][35] These data argued against interruptions to ART to prevent serious non-AIDS events and a need to understand links between specific antiretroviral drugs and the risk of cardiovascular disease. Furthermore, observational data linking untreated HIV with increased levels of chronic inflammation and poor clinical outcomes were increasingly reported.[36][37]

Since the change in US guidelines in 2007 to recommend ART for all PLHIV with CD4  cell counts below 350/μL, additional observational studies and randomised trials have examined whether starting ART at higher CD4 cell counts offers clinical benefit.[38][39][40][41][42] These observational data from American and European cohorts, supported by a later secondary analysis from the HPTN 052 study, performed predominantly in low-to-medium income countries, report a benefit in preventing AIDS-defining illnesses, with some of the observational analyses also reporting a survival benefit. These studies led to changes in the 2009 US recommendations to initiate ART in all people with CD4 cell counts  less than 500/μL. 

Subsequent to these guideline change, the HPTN 052 study reported a 96% reduction in the risk of HIV transmission between serodiscordant heterosexual couples due to ART, ushering in the era of ‘treatment as prevention’.[43] The benefits of ART to prevent transmission were further supported by preliminary analyses in cohorts of male serodiscordant couples that reported no linked transmissions.[44][45]  In 2016 the results of the START study that randomised 4685 PLHIV with CD4 cell counts above 500 cells/μL to initiate ART immediately or defer until CD4 counts were below 350/μL was reported. This study demonstrated a 57% risk reduction in the primary endpoint that combined serious AIDS and non-AIDS events and provided level 1 evidence (Table 1) on the benefits of ART for all PLHIV and resulted in concordance among treatment guidelines in the USA, Europe and from the World Health Organization to recommend ART initiation in all PLHIV regardless of CD4 count.[46] The ASHM Sub-Committee for Guidance on HIV Management in Australia prepares the commentary to the DHHS guidelines; it provides specific recommendations for the Australian setting on the topic of ART initiation and also provides a comparison of recommendations in international guidelines on when to start ART.[47] The Sub-Committee also recommends ART for all people with HIV infection, irrespective of CD4 count, based on level 1 evidence (Table 1).

Table 1. Rating scheme for recommendations in the US Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents[48]
Strength of recommendation Quality of evidence for recommendation

A:  Strong recommendation for the statement

B:  Moderate recommendation for the   statement

C:  Optional recommendation for the statement

 I:  One or more randomized trials with clinical outcomes and/or validated laboratory endpoints

II:  One or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes

III:  Expert opinion

Goals of therapy

Eradication of HIV is not achievable with currently available antiretroviral agents, so management focuses on controlling HIV replication with chronic suppressive therapy. 

When initiating ART the primary goals of therapy are to:[49]

  • maximally and durably suppress plasma HIV viral load
  • reduce HIV-associated morbidity and prolong the duration and quality of survival
  • restore and preserve immunological function
  • prevent HIV transmission.

ART is able to reduce plasma HIV viral load to below the limits of quantification of the licensed test, also referred to as viral or virological suppression.[50][51] This definition has changed as tests became more sensitive, so the DHHS guidelines now define optimal viral suppression as a viral load persistently below the level of detection; HIV RNA less than 20 to 75 copies/mL, depending on the assay used.[52] This level of suppression is associated with improvements in survival and clinical outcomes although the absolute plasma viral load threshold in someone fully adherent to therapy that will provide long-term treatment success is unknown.[53] In addition improvements in CD4 cell count are significant predictors of prolonged survival and prevention of progression to new AIDS-defining illnesses. These findings are independent of changes in viral load, indicating that people with immune restoration but without adequate viral suppression are still receiving benefit from ART.[54][55] It should be noted however that up to one third of patients receiving ART fail to restore the CD4 cell count to above 500 cells/μL despite full virological suppression.[56] Predictors of poorer immune restoration include older age, longer duration of HIV-infection, lower baseline CD4  cell count, prior AIDS, and persistent immune activation.[57][58] Furthermore there are no known effective therapies including switching ART and immune-based therapies such as interleukin-2 to provide additional immune restoration.[59] Despite the risk of worse long-term outcomes with poor CD4 cell recovery, virological suppression from ART provides significant long-term clinical benefit.[60]

Ideally, these goals of therapy would be achieved without additional morbidity or mortality from drug-related adverse events. Unfortunately, this is not always possible and much of the current management of patients with HIV disease involves managing therapy associated toxicities. The latter is especially true of highly treatment-experienced patients in whom toxicities from older antiretroviral agents and multidrug resistance pose unique challenges. In situations of multidrug resistance, viral suppression and immune preservation are greater immediate priorities than ART-associated toxicity.

In ART-naïve patients initiating therapy, other factors are also relevant in achieving the goals of therapy. These include the use of baseline resistance testing to detect transmitted HIV drug resistance and in order to avoid the use of antiretroviral agents ineffective for resistant strains, and maximising adherence to the antiretroviral regimen. A patient’s ability to adhere to a regimen is critical for successful treatment as poor adherence can lead to: virological failure, the development of HIV-drug resistance mutations and decreased patient survival.[61][62][63][64] It is therefore important to consider factors such as toxicity, pill burden and dietary restrictions which may aect the ability of a patient to adhere to a given regimen. Other important factors include co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)  and illicit substance and alcohol use.[65][66] The former is included because the toxicity of some antiretroviral agents is worse in the setting of viral hepatitis co-infection,[67] and the latter because of greater risk of non-adherence and the potential for drug interactions. 

Antiretroviral agents

Antiretroviral therapy has evolved considerably since the introduction of zidovudine in 1987. The subsequent development of five additional drug classes has resulted in the availability of at least 20 agents for use in combination regimens.

The six classes of antiretroviral drugs currently licensed for use in Australia are:

•           Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI)

•           Non-nucleoside reverse transcriptase inhibitors (NNRTI)

•           Protease inhibitors (PI)

•           Integrase inhibitors

•           Entry inhibitors: Fusion inhibitors

•           Entry inhibitors: CCR5 inhibitors

For treatment of ART- naïve patients, there are now several combinations of drugs recommended in the DHHS guidelines, although there is some variability in recommendations for initial therapy in other major guideline from the US and Europe.[68][69] The DHHS guidelines also have two more categories ‘Alternative’ and ‘Other’ which include regimens that may be optimal for a treatment-naïve patient depending on individual patient characteristics.

The six regimens currently recommended combine a two-drug NRTI backbone with a third antiretroviral agent from a different class as follows:

Integrase strand transfer inhibitor-based regimens

• Dolutegravir/abacavir/lamivudine

• Dolutegravir plus tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine 

• Raltegravir plus tenofovir DF/emtricitabine 

• Elvitegravir/cobicistat/tenofovir DF/emtricitabine

• Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine

Protease inhibitor-based regimen

• Darunavir/ritonavir plus tenofovir DF/emtricitabine 

Notably, cobicistat is not an antiretroviral agent but is included in the above regimens as a pharmaco-enhancer. Cobicistat is a CYP3A inhibitor that increases systemic exposure to antiretroviral agents including elvitegravir, atazanavir and darunavir so that they can be administered  once daily. However the PI/cobicistat combinations are not currently available in Australia but darunavir/cobicistat may be available by mid-2016. In addition to the above recommended regimens, two US and one European guideline panel (DHHS, International Antiviral Society [IAS]-USA and the European AIDS Clinical Society [EACS]) have listed NRTI-sparing regimens as alternatives since July 2014. Specifically, they have considered raltegravir plus either ritonavir-boosted lopinavir or ritonavir-boosted darunavir, lamivudine plus ritonavir-boosted lopinavir as alternative regimens. Further combinations of a two-drug NRTI backbone and a third agent from a different class are also listed as alternatives.[70][71][72]

In addition to antiretroviral agents already mentioned that are recommended for treatment initiation, there are other medications largely reserved for the treatment of drug-resistant strains of HIV including: maraviroc, etravirine and enfuvirtide. New regimens that include these types of antiretroviral agents in treatment-experienced patients with virological failure should include at least two, and preferably three, fully active agents. In this context an agent is expected to have full activity based on the patient’s prior treatment history and drug-resistance testing results. Furthermore many older antiretroviral agents are now not recommended as initial therapy due to toxicity or concerns of poor efficacy but are still available on the Pharmaceutical Benefits Scheme (PBS), namely: stavudine, didanosine, zidovudine, nevirapine and some ritonavir-booster PIs (indinavir, saquinavir, fosamprenavir, tipranavir). Notably many people commenced these older agents before newer agents have become available and have been maintained on treatment for many years.

Antiretroviral classes

Nucleoside and nucleotide reverse transcriptase inhibitors

The    NRTIs    interfere    with    the RNA-dependent DNA polymerase (reverse transcriptase) of HIV by acting as structural analogues for thymidine or adenosine when DNA is reverse transcribed inside cells leading to premature DNA chain termination and inhibition of viral replication.  All NRTIs have the potential to inhibit human intracellular DNA   polymerase   necessary for mitochondria to replicate. Inhibition of this function leads to many of the potential toxicities of this class of drug, particularly with older agents. The nucleoside analogues are lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), zidovudine (AZT), didanosine (ddI) and stavudine (d4T). Tenofovir disoproxil fumarate (tenofovir DF or TDF) and tenofovir alafenamide fumarate (TAF) are orally bioavailable prodrugs of tenofovir, that are metabolised intracellularly into the active metabolite, tenofovir diphosphate. TAF is an alternative prodrug to TDF that is preferentially metabolised into the active metabolite in lymphocytes allowing lower systemic doses to be administered that minimise toxicity without compromising virological efficacy. Emtricitabine, lamivudine, TDF and TAF also display activity against HBV.

Importantly, many agents in this class are available as fixed-dose combination (FDC) tablets. These agents include earlier FDCs such as zidovudine plus lamivudine (Combivir™), and zidovudine/lamivudine/abacavir (Trizivir™), then subsequently the currently recommended NRTI backbones of tenofovir DF/emtricitabine (Truvada™) and abacavir/lamivudine (Kivexa™).  Moreover, tenofovir DF/emtricitabine has been coformulated with: efavirenz (Atripla™), rilpivirine (Eviplera™) and with elvitegravir/cobicistat (Stribild™). Also available are elvitegravir/cobicistat coformulated with tenofovir alafenamide/emtricitabine (Genvoya™) and abacavir/lamivudine coformulated with dolutegravir (TriumeqTM).

Importantly, the only N(t)RTIs currently recommended for initial therapy by US and European guidelines are the combinations of abacavir plus lamivudine and tenofovir (TDF or TAF) plus emtricitabine. TAF is currently only approved for use in Australia when coformulated with elvitegravir/cobicistat. It should be noted that abacavir should only be prescribed to people who test negative for HLA-B*5701, which accurately predicts the development of abacavir hypersensitivity,[73] a severe and potentially life-threatening reaction which occurs in 5-8% of those exposed to the drug. There are no recommendations for the other listed NRTIs, including all older thymidine analogues, even as an alternative largely because of toxicity including; peripheral neuropathy, lipoatrophy, pancreatitis and lactic acidosis.

A guide to dosing of NRTIs can be found in Table 2 and a guide to adverse effects in Table 3. 

Table 2 Guide to nucleoside reverse transcriptase inhibitors dosing[74]
Drug (dose per tablet) Dosing Food requirement Dose adjustment for renal impairment Dose adjustment for hepatic impairment
Abacavir (ABC) (300 mg)

300 mg bd or

600 mg qd

No No No
Emtricitabine (FTC) (200 mg) 200 mg qd No Yes* No
Lamivudine (3TC) (300 mg or150 mg)

300 mg qd

150 mg bd

No Yes* No
Tenofovir (TDF) (300 mg) 300 mg qd No Yes* No
Didanosine (ddI) (250 mg or 400 mg)

400 mg qd if >60 kg

250 mg qd if <60 kg

Take 30 minutes before food or 2 hours post meal Yes* No
Stavudine (d4T) (40mg or 30mg)

40 mg bd if
> 60 kg

30 mg bd if
< 60 kg

No Yes* No
Zidovudine (AZT) (250 mg) 250 mg bd No Yes (very severe impairment) * No
Coformulated preparations

Kivexa™

(ABC 600 mg/ 3TC 300 mg)

One tablet qd No Yes - do not use if CrCl
< 50 mL/min
No

Truvada™

(TDF 300 mg/ FTC 200 mg)

One tablet qd No Yes. CrCl 30-49 mL/min
1 tablet  every 48h. Do not use if CrCl < 30 mL/min
No

Combivir™

(AZT 300 mg / 3TC150 mg)

One tablet bd No Yes. Do not use if CrCl < 50 mL/min No

Atripla™

(TDF 300 mg/ FTC 200 mg/ EFV 600 mg)

One tablet qd nocte Take at night on empty stomach to reduce side effects Yes. Do not use if CrCl < 50 mL/min Use with caution

Eviplera™

(TDF 300 mg/ FTC 200 mg/ RPV 25 mg)

One tablet qd Take with a meal Yes. Do not use if CrCl < 50 mL/min No

Stribild™

(TDF 300 mg/ FTC 200 mg/ EVG 150 mg/ cobicistat 150 mg)

One tablet qd Take with food Yes. Do not initiate if CrCl < 70 mL/min Do not use if severe insufficiency

#Genvoya™

(TAF 10 mg/ FTC 200 mg/ EVG 150 mg/ cobicistat 150 mg)

One tablet qd Take with food Yes. Do not initiate if CrCl < 30 mL/min Do not use if severe insufficiency
* check product information for change in dosing according to creatinine clearance
qd: once daily; bd: twice daily; nocte: at night; CrCl: creatinine clearance; EFV: efavirenz; RPV: rilpivirine; EVG: elvitegravir; TAF: tenofovir alafenamide fumarate
# TGA approved and likely to be listed on PBS in March/April 2016

 

Table 3 Adverse effects of nucleoside reverse transcriptase inhibitors [75]
Drug Adverse effect Potentially life-threatening adverse effect

Abacavir (ABC)

Also available as part of a FDC

Usually minimal toxicity

HSRs: at highest risk if test positive for HLA- *5701. HLA screening prior to initiation of ABC.

Rechallenge not recommended.

HSR symptoms include: fever, rash,nausea, vomiting, diarrhoea, abdominal pain, malaise or respiratory symptoms

Risk of MI associated with recent or current use

Emtricitabine (FTC)

Also available as part of a FDC

Minimal toxicit

Hyperpigmentation

/ skin discolouration

Severe acute exacerbation of hepatitis may occur in patients with HBV co-infection who discontinue FTC

Lamivudine(3TC)

Also available as part of a FDC

Minimaltoxicity Severe acute exacerbation of hepatitis may occur in patients with HBV co-infection who discontinue FTC

Tenofovir (TDF)

Also available as part of a FDC

  • Asthenia,
  • headache,
  • diarrhoea,
  • nausea,
  • vomiting and flatulence

 

  • Renal insufficiency,
  • Fanconi syndrome,
  • proximal tubulopathy

Osteomalacia, decrease in bone mineral density

Potential decrease in bone mineral density

Severe acute exacerbation of hepatitis may occur in patients with HBV co-infection who discontinue TDF

 

Fanconi syndrome

Didanosine(ddI)

Peripheral neuropathy

Nausea

Retinal changes, optic neuritis

Insulin resistance/diabetes mellitus

Pancreatitis

Rarely lacticacidosis with hepaticsteatosis

Stavudine (d4T)

Peripheral neuropathy

Lipoatrophy

Hyperlipidaemia

Nausea

Retinal changes, optic neuritis

Insulin resistance / diabetes mellitus

Pancreatitis

Rarely lacticacidosis with hepatic steatosis

Rapidly progressive ascending neuro muscular weakness

Zidovudine(AZT)

Also available as part of a FDC

Gastrointestinal intolerance, headacheinsomnia,asthenia

Nail pigmentation

Lipoatrophy

Hyperlipidaemia

Insulin resistance / diabetes mellitus

Myopathy

Bone marrow suppression: macrocytic anaemiaor neutropenia (can be severe)

Rarely lacticacidosis with hepatic steatosis

bd: twicedaily, HSR: hypersensitivity reaction; FDC: fixed dose combination; MI: myocardial infarct

Non-nucleoside reverse transcriptase inhibitors

The NNRTI class includes efavirenz (EFV), rilpivirine (RPV), etravirine (ETV) and nevirapine (NVP). A guide to dosing of NNRTI can be found in Table 4 and a guide to adverse effects in Table 5. NNRTIs bind directly to the reverse transcriptase enzyme and block the RNA-dependent and DNA-dependent polymerase activities by causing a disruption of the enzyme’s catalytic site. This reduces enzyme activity and diminishes viral replication. Importantly NNRTIs are not active against HIV-2 as the reverse transcriptase binding site has a different structure and they do not inhibit human DNA polymerases as do NRTIs. Furthermore, as a class, NNRTIs are considered to have a low genetic barrier to the development of HIV drug resistance with suboptimal adherence and treatment interruptions of as little as 48 hours to selection of single mutations that confer high-level resistance to these agents.[76]

Nevirapine was the first NNRTI developed for use in PLHIV and while it remains an effective antiretroviral agent it is currently not recommended for initiation due to the risk of hepatotoxicity, especially in women with a CD4 cell count at or above 250 cells/μL and men with a CD4 -cell count at or above 400 cells/μL. Efavirenz was the next NNRTI available and from the late 1990s until 2015 was a recommended third agent to add to an NRTI backbone in all major guidelines and now is the recommended third agent in the World Health Organization (WHO) guidelines targeted at low-middle income countries.[77] It was removed from the recommended category of the 2015 DHHS guidelines as a result of the availability of equipotent and better tolerated agents available as single dose FDCs.

Etravirine and rilpivirine are second-generation NNRTIs that have ecacy in the presence of the classic NNRTI resistance mutation K103N.  The virological impact of these agents diminishes in the presence of other NNRTI mutations (of which 15 have been identified) that each confer variable impact on virological efficacy.[78] Rilpivirine is also available in a once-daily coformulated tablet, with US and European guideline panels recommending initiation of rilpivirine if baseline viral load is below 100,000 copies/mL based on increased numbers of virological failures in this high viral load group despite a lower side effect profile than efavirenz.[79] Conversely etravirine has been principally studied in people with previous virological failure and HIV drug resistance and is not recommended for ART-naïve people but for use in treatment-experienced people with resistance to multiple antiretroviral agent classes in conjunction with a boosted protease inhibitor.[80][81]

 Table 4  Guide to non-nucleoside reverse transcriptase inhibitors dosing[82]
Drug (dose per tablet) Dosing Food requirement Dose adjustment for renal impairment Dose adjustment for hepatic impairment
Efavirenz (EFV) (600 mg or 200mg)
Also available in a FDC (Table 2)
600 mg qd nocte Take at night on empty stomach to reduce side-effects. No Use with caution
Etravirine (ETV) (100 mg) 200 mg bd Yes Use with caution No
Rilpivirine (RPV) (25 mg)
Also available in a FDC (Table 5.1)
25 mg qd Take with a meal No No
Nevirapine (NVP) (200 mg or 400 mg XR) 200 mg bd
or 400 mg XR qd (after initiation with 200 mg qd for 14 days)
No No Contraindicated in Child-Pugh class B or C
qd: once daily; bd: twice daily; nocte: at night; tds: three times daily; XR: extended release;

 

 Table 5 Adverse effects of non-nucleoside reverse transcriptase inhibitors[83]
Drug Adverse effect Potentially life-threatening adverse effect
Efavirenz(EFV)
Also available as part of a FDC
Rash (SJS very rare)
Neuropsychiatric symptoms (dizziness, somnolence, insomnia, abnormal dreams, depression, suicidality, confusion, abnormal thinking, impaired concentration, amnesia, agitation, hallucinations, and euphoria)
Increased transaminase levels
Hyperlipidaemia
False-positive results with some cannabinoid and benzodiazepine screening assays reported
2%report severe depression
Potentially teratogenic in humans
Etravirine(ETV) Rash (SJS very rare)
Nausea
HSRs: rash, constitutional findings, and sometimes organ dysfunction,including hepatic failure are reported
Rilpivirine (RPV)
Also available as part of a FDC
Rash (SJS very rare)
Depression, insomnia, headache
Hepatotoxicity
None
Nevirapine(NVP) Rash
Fever
Nausea
Headache
Increased transaminase levels
SJS (rare)
Symptomatic hepatitis , including fatal hepatic necrosis

FDC: fixed dose combination; SJS: Stevens-Johnson syndrome; HSR: hypersensitivity reaction

Protease inhibitors

The PIs inhibit HIV-1 and HIV-2 proteases and prevent cleavage of the gag-pol polyprotein that occurs during maturation of the newly formed viral particle. This results in the production of immature, non-infectious virus.  There are currently seven licensed  PIs:  atazanavir  (ATV),  darunavir (DRV), fosamprenavir  (FOS),  coformulated lopinavir/ritonavir (LPV/r), ritonavir (RTV), saquinavir (SQV) and tipranavir (TPV). Ritonavir is not used for its antiretroviral activity; rather, it is used as a pharmaco-enhancer by exploiting its inhibition of cytochrome p-450 (3A4) enzyme to boost levels of concomitantly administered PIs. This action also can lead to interactions with concomitant medications metabolised by the same enzymatic system (Table 6). A guide to dosing of PIs can be found in Table 6 and a guide to adverse effects in Table 7.The usual dose of ritonavir to increase the effect of protease inhibitors is 100 mg once daily or 100-200 mg twice daily, depending on the PI being boosted (referred to as PI/r). Furthermore, ritonavir boosting increases plasma levels of PIs to levels greatly above what is required to inhibit viral replication even in the setting of one or two PI mutations. This means the development of PI resistance is much less likely to occur for a given level of adherence and is also referred to as a high-genetic barrier to resistance.[84] Third generation PIs include ritonavir-boosted darunavir and tipranavir which are licensed for use in patients with multidrug resistant virus.[85][86] Boosted darunavir is also licensed for use with once daily dosing in ART-naïve patients and treatment-experienced patients with no darunavir resistance associated mutations.[87] Of this antiretroviral class only darunavir is recommended for treatment initiation largely because of different adverse effects seen with other agents in this class, including: hyperlipidaemia, hyperglycaemia, fat maldistribution, diarrhoea and hepatotoxicity. Furthermore atazanavir and darunavir will become available coformulated with cobicistat, the non-protease inhibitor of cytochrome p450, instead of ritonavir. There is also a plan to include darunavir in a coformulated single tablet regimen with cobicistat, tenofovir alafenamide and emtricitabine.

 Table 6 Guide to protease inhibitor dosing[88]
Drug Dosing Food requirement Dose adjustment for renal impairment Dose adjustment for hepatic impairment
Atazanavir (ATV) (300 mg or 400 mg) 300 mg qd with RTV 100 mg qd or 400 mg qd without RTV Do not use without RTV with tenofovir DF or in treatment-experienced patients Yes, avoid antacids, H2 antagonists and proton pump inhibitors. Seek expert advice if unsure No Not recommended if Child-Pugh class C. If Child-Pugh class B use ATV (300 mg) qd (without ritonavir)
Darunavir (DRV) (600 mg or 800 mg) 800 mg qd with RTV 100 mg qd or 600 mg bd with RTV 100 mg bd if DRV-associated mutations Yes No Not recommended if severe hepatic impairment
Fosamprenavir (FPV) (700 mg) 1400 mg qd with RTV 100 mg qd for ART naïve 700 mg bd with RTV 100 mg bd for treatment experienced. Without RTV take without regard to meals. With RTV take with meals. No Complex. Seek expert advice. Dose reduction as Child-Pugh score increases
Lopinavir/ ritonavir (LPV/r) (200 mg/50 mg) 400 mg/100 mg bd or 800 mg/ 200 mg qd (if < 3 lopinavir-associated mutations) No No Use with caution
saquinavir (SQV) (500 mg) 1g bd with RTV 100 mg bd Take within 2 hours of food No Use with caution: mild-mod impairment. Contraindicated in severe impairment
Tipranavir (TPV) (250 mg) 500 mg bd with RTV 200 mg bd Take with meals No Use with caution Contraindicated Child-Pugh class B and C
qd: once daily; bd: twice daily; ART: antiretroviral treatment; RTV: ritonavir; tenofovir DF: tenofovir disoproxil fumarate

 

Table 7 Adverse effects of protease inhibitors[89]
Drug Adverse effect Potentially life-threatening adverse effect
Atazanavir (ATV)
  • Indirect hyperbilirubinaemia
  • Hyperglycaemia
  • Hyperlipidaemia
  • Fat maldistribution
  • Cholelithiasis
  • Nephrolithiasis
  • Renal insufficiency
  • Transaminase elevations
  • Skin rash
Prolonged PR interval-1st degree symptomatic AV block in some patients; use with caution in patients with conduction defects or on medications that cause PR prolongation
darunavir (DRV)*
  • Skinrash(10%); DRVhas sulfonamide moiety
  • Hepatotoxicity
  • Diarrhoea,
  • Nausea
  • Headache
  • Hyperglycaemia
  • Hyperlipidaemia
  • Transaminase elevations
SJS, toxic epidermal necrolysis, acute generalised exanthematous pustulosis and erythrema multiforme have been reported (rare)
Fosamprenavir(FOS)
  • Skin rash (12-19%); FPV has sulfonamide moiety
  • Diarrhoea
  • Nausea
  • Vomiting
  • Headache
  • Hyperglycaemia
  • Hyperlipidaemia
  • Fatmaldistribution
  • Transaminase elevations
  • Nephrolithiasis
Possible increased bleeding episodes in patients with haemophilia
Lopinavir/ritonavir(LPV/r) GIintolerance: nausea, vomiting, diarrhoea
Asthenia
Hyperlipidaemia especially hypertrigly ceridaemia
Hyperglycaemia
Fatmaldistribution
Transaminase elevations

PR interval prolongation

QT interval prolongation and torsades de pointes reported

Pancreatitis

Possible increased bleeding episodes in patients with haemophilia

Ritonavir (RTV)(boosting) GI intolerance,nausea, vomiting, diarrhoea
Paresthesias–circumoraland extremities
Hyperlipidaemia especially hypertriglyceridaemia
Hyperglycaemia
Fatmaldistribution
Hepatitis
Asthenia
Tasteperversion
Caution with drug-drug interaction for drugs with a narrow therapeutic index Possible increased bleeding episodes in patients with haemophilia
Saquinavir (SQV)* GI intolerance:nausea,diarrhoea
Headache
Hyperlipidaemia especially hypertriglyceridaemia
Hyperglycaemia
Fatmaldistribution
Transaminase elevations

PR interval prolongation

QT interval prolongation and torsades de pointes reported

Pancreatitis

Possible increased bleeding episodes in patients with haemophilia

Tipranavir (TPV)* Hepatotoxicity
Skinrash 2–21% TPV has a sulfonamidemoiety
Hyperlipidaemia especially hypertriglyceridaemia
Hyperglycaemia
Fatmaldistribution

Clinical hepatitis including hepatic decompensation has been reported ,especially in patients with underlying liver disease

Rare cases of fatal and non-fatal intracranial haemorrhages reported. Most patients had underlying comorbidity including: brain lesion, head trauma, recent neurosurgery, coagulopathy, hypertension, alcoholism or medication with risk for bleeding

Possible increased bleeding episodes in patients with haemophilia

*can only be administered with boosting doses of ritonavir; SJS=Stevens-Johnson syndrome; AV: atrioventricular

Integrase inhibitors

Integrase strand transfer inhibitors (INSTIs) prevent the integration of HIV DNA into the nucleus of the host cell. Elvitegravir is only available in Australia as part of an FDC with tenofovir, emtricitabine and cobicistat, unlike raltegravir and dolutegravir which are available as individual medications. All three INSTIs are metabolised by glucuronidation via the enzyme UDP-glucuronosyltransferases (UGT1A1) to varying degrees influencing their potential for drug interactions with medications metabolised by cytochrome p450 enzymes. Raltegravir is exclusively metabolised by UGT1A1 whereas dolutegravir also has some elimination by CYP3A4 and elvitegravir is primarily metabolised by cytochrome p450 with a minor contribution from UGT1A1. The potential for drug-drug interactions is greater when metabolised by cytochrome p450 enzymes, except for some circumstances when coadministered with potent UGT1A1 inducers such as rifampicin. A guide to Integrase strand transfer inhibitor dosing can be found in Table 8 and adverse effects in Table 9.

 Table 8  Guide to integrase inhibitor dosing[90]
Drug (dose per tablet) Dosing Food requirement Dose adjustment for renal impairment Dose adjustment for hepatic impairment
Dolutegravir (DTG) (50 mg) 50 mg qd or 50 mg bd if proven/suspected InSTI resistance No No Not recommended If Child-Pugh class C

Evitegravir (EVG)

Only available in a FDC (Table 2)               

Table 2 Table 2 Table 2 Table 2
Raltegravir(RAL)(400mg) 400mg bd No No No

Qd: once daily; bd: twice daily; FDC: fixed dose combination

 

Table 9 Adverse effects of integrase inhibitors[91]
Drug Adverse effect Potentially life-threatening adverse effect
Dolutegravir (DTG) Insomnia
Headache
HSRs including rash, constitutional symptoms and organ dysfunction (including liver injury) reported
Elvitegravir (EVG)
Only available in a FDC


Nausea
Diarrhoea
New onset or worsening renal impairment*
Potential decrease in bone mineral density

Severe acute exacerbation of hepatitis may occur in patients with HBV coinfection who discontinue FTC and TDF
Raltegravir(RAL)
  • Nausea
    Headache
  • Diarrhoea
  • Pyrexia
  • Creatine phosphoskinase elevation
  • Rash, including SJS, HSR and toxic epidermal necrolysis reported
  • Necrolysis reported
  • Rhabdomyolysis

SJS: Stevens-Johnson syndrome; HSR: hypersensitivity reaction; FDC: fixed dose combination; HBV: hepatitis B virus; FTC: emtricitabine; TDF: tenofovir disoproxil fumarate

*These adverse effects are not specific to elvitegravir but a consequence of other agents in the fixed dose combination

Entry inhibitors

HIV entry is a complex, multistep process, and can be considered under the following basic steps which provide different targets for antiretroviral agents:

  • Binding of HIV to CD4 receptor via the gp120 subunit of the envelope protein
  • Structural change in gp120, allowing it to bind to chemokine co-receptors CCR5 or CXCR4
  • Gp41-mediated fusion of the viral envelope with the cell membrane, completing viral entry.

Two antiretrovirals have been developed that act as entry inhibitors, forming two separate classes; the fusion inhibitor enfuvirtide and the CCR5-receptor antagonist maraviroc.

Fusion inhibitors

Enfuvirtide (T-20) is a synthetic 36-amino acid peptide analogue. It binds to gp41, interrupting  the  fusion  reaction  and  preventing  the virus  from  infecting  the  host  cell. Enfuvirtide, an injectable agent, is licensed for patients with multidrug resistant virus based on two key trials.[92][93]The main disadvantage of enfuvirtide is the universal development of injection site reactions, which are unpleasant for the patient, and appear to be associated with skin sclerosis with long-term use.   Other side effects are listed in Table 11 and dosing of fusion inhibitors in Table 10.

Table 10     Guide to fusion inhibitor dosing[94]

Drug (dose perinjection)

Dosing

Food requirement

Dose adjustment for renal impairment

Dose adjustment for hepatic impairment

Enfuvirtide (T-20) (90 mg)

90mg subcutaneous injection twice dialy

No

No

No

 

 Table 11      Adverse effects of fusion inhibitors[95]

Drug

Adverseeffect

Potentially life- threatening adverse effects

Enfuvirtide (T-20)

Local injection site reactions – almost 100% of patients (pain, erythema, induration, nodules and cysts, pruritus, ecchymosis)

Increased rate o fbacterial pneumonia

Hypersensitivity reaction (< 1%): symptoms may include rash, fever, nausea,vomiting,chills,rigors, hypotension, or elevated serum transaminases. Rechallenge not recommended

CCR5 inhibitors

The development of CCR5 inhibitors arose from the recognition that CCR5 is a key receptor for HIV,[96] at least early on in the disease, and that genetic absence (delta 32 homozygosity) was associated with protection against HIV infection.[97] Moreover, people with reduced levels of CCR5 (delta 32 heterozygotes) have an attenuated disease course with lower HIV viral load.[98]

These drugs are allosteric inhibitors that lock CCR5 into a conformation such that it is not able to bind HIV envelope protein. Maraviroc is only effective in patients whose virus utilises CCR5 for cell entry (R5 tropic), and special tropism testing is mandated before the use of this drug.[99][100] There is no virological efficacy in patients with CXCR4 (X4) or dual tropic HIV. A guide to dosing of maraviroc can be found in Table 12 and adverse effects of maraviroc in Table 13.

 Table 12 Guide to CCR5 inhibitors dosing[101]
Drug (dose per tablet) Dosing Food requirement Dose adjustment for renal impairment Dose adjustment for hepatic impairment

Maraviroc (MVC) (150mg and 300mg)

  • 150 mg bd when given with all PI/r except tipranavir/r

  • 300 mg bd when given with NRTIs, enfuvirtide, NVP, tipranavir/r, raltegravir and other non-potent CYP3A inhibitors or inducers

  • 600 mg bd when given with CYP3A inducers including efavirenz and etravirine

No

Complex. If CrCL < 30mL/min:

  • Without potent CYP3A inhibitors or inducers -> 300 mg bd; reduce to 150 mg bd if postural hypotension occurs
  • With potent CYP3A inducers or inhibitors -> not recommended

Concentration likely to be increased in hepatic impairment

bd: twice daily; CrCL: creatinine clearance; CYP3A: hepatic cytochrome p450 enzyme 3A; PI/r: protease inhibitor boosted with ritonavir; NRTI: nucleoside reverse transcriptase inhibitor

 

 Table 13 Adverse effects of  CCR5 inhibitors[102]
Drug Adverse effect Potentially life-threatening adverse effect
Maraviroc (MVC)

Abdominalpain
Cough
Dizziness
Musculoskeletalsymptoms
Pyrexia
Rash
Upperrespiratorytractinfections
Hepatotoxicity
Orthostatic hypotension, especially in patients with severe renal insufficiency

None

New antiretroviral agents

New antiretroviral agents in the existing classes are being developed with the aim of producing drugs with more favourable toxicity profiles and activity against drug-resistant virus. These include a new NNRTI doravirine (Phase III) and a new CCR5 inhibiter cenicriviroc (Phase III) that also has activity blocking CCR2. There is also a monoclonal antibody directed against CCR5 (PRO 140) currently under development in in Phase II trials that is administered subcutaneously. Current new classes of agents in Phase II stage of development are the attachment inhibitor fostemsavir that binds to the gp120 protein on HIV-1 interfering with its ability to bind to the CD4 cell receptor and maturation inhibitor BMS-9551.[103] Maturation inhibitors block a step in the processing of the group-specific antigen (Gag) polyprotein, necessary for virion maturation, leading to the release of immature non-infectious virions. In addition to new antiretroviral agents in current classes, or in new classes, there are multiple pending compounds based on currently available antiretroviral agents. These include: long acting injectable versions of rilpivirine (Phase I) and a dolutegravir analogue (cabotegravir) that is being developed in long-acting injectable and oral forms (Phase II).

Antiretroviral regimens

Combination therapy with at least three drugs is now standard treatment for patients with HIV starting ART for the first time. The DHHS guidelines recommend a two NRTI backbone with another antiretroviral agent from a different class, either: an integrase inhibitor or ritonavir-boosted darunavir. The rationale for these recommendations is based upon randomised clinical trials and long-term safety data, summarised in the guidelines.[104] Triple-NRTI combinations, such as abacavir, zidovudine and lamivudine (Trizivir™) and ritonavir-boosted PI monotherapy are best avoided because of inferior virological efficacy when compared to traditional three-drug regimens.[105][106] Data from large trials examining the efficacy of NRTI-sparing regimens against traditional three-drug regimens with an NRTI backbone are now available. NRTI-sparing regimens may be attractive for people positive for HLA*B5701 or those with comorbidities including cardiovascular disease, renal failure or osteoporosis. The largest randomised studies have combined a ritonavir-boosted PI with an integrase inhibitor, and one study combined the least toxic NRTI, lamivudine, with ritonavir-boosted lopinavir.[107][108][109]The study comparing ritonavir-boosted darunavir plus raltegravir to ritonavir-boosted darunavir plus tenofovir/emtricitabine in treatment initiation revealed these two regimens to be non-inferior. However a subgroup analysis of people with CD4 cell counts  below 200 cells/ μL showed the NRTI-sparing arm to be less efficacious, particularly in this subgroup with baseline viral load above 100,000 copies/mL.[110] Guidelines on dosing of antiretroviral agents are shown in Tables 2, 4, 6, 8,10, and 12. Antiretroviral regimens or components that should not be offered at any time are shown in Table 14

 Table 14 Antiretroviral regimens or components that should not be offered at any time (see the DHHS guidelines for exceptions)[111]
Anti retroviral regimens not recommended Rationale

Monotherapy with NRTI

Inferior virological activity plus rapid development of resistance

Dual-NRTIregimens

Inferior virological activity plus rapid development of resistance

Triple-NRTIregimens

High rate of early virological nonresponse
Only exceptions are abacavir/zidovudine/lamivudine and possibly tenofovir disoproxil fumarate + zidovudine/lamivudine (Evidence: BII) in patients in whom other combinations are not desirable

 
Anti retroviral components not recommended as part of an antiretroviral therapy regimen Rationale

Didanosine (ddI) and stavudine (d4T)

Higher incidence of overlapping toxicities including pancreatitis, peripheral neuropathy, lacticacidosis, lipodystrophy

Didanosine (ddI) and tenofovir (TDF)

Increased ddI concentrations and serious ddI-associated toxicities, high rate of early virological failure, rapid selection of resistance at failure

Efavirenz (EFV) in first trimester of pregnancy

Teratogenicinnon-humanprimates. Exception only if no other antiretroviral options are available and potential benefits outweigh the risks

Nevirapine (NVP)  inART-naïve women and men with CD4 cellcount  ≥ 250 cells/μL and 400 cells/μL respectively

Greaterriskofsevere,life-threateninghepatotoxicity

Unboostedsaquinavir(SQV), darunavir (DRV) or tipranavir (TPV)

Inadequate bioavailability

Stavudine(d4T)with zidovudine(AZT)

Antagonistic effect on HIV-1

Nevirapine(NVP)  +efavirenz(EFV), ornevirapine (NVP) / efavirenz(EFV) + etravirine

Higher incidence o ftoxicity

Emtricitabine (FTC) + lamivudine (3TC)

Similar resistance profiles, no potential benefit

Etravirine (ETR) + unboosted PI

ETR may induce metabolism of these PIs; appropriate doses not yet established

Etravirine (ETR) + ritonavir-boosted atazanavir (ATV/r) or fosamprenavir (FPV/r)

ETR may alter the concentrations of these PIs; appropriate doses not yet established

etravirine (ETR) + ritonavir-boosted tipranavir (TPV/r)

ETR concentration may be significantly reduced by ritonavir -boosted TPV

Adverse effects of antiretroviral agents

Adverse effects for NRTI, NNRTI, PI, INSTI, fusion inhibitors and CCR5-antagonists, are found in Tables 3, 5, 8, 10, 11 and 14, respectively.

In addition to the above listed adverse effects, cobicistat, dolutegravir and to a lesser extent rilpivirine can increase serum creatinine through inhibition of creatinine secretion but there is no reduction in glomerular filtration as demonstrated by renal iohexol clearance. The average increase in serum creatinine reported with cobicistat and dolutegravir is 10-13 μmol/L, seen over the first 2-8 weeks after initiation and then stabilising thereafter.[112][113] There is a normal range around these creatinine increases; however the DHHS guideline group recommends that an increase of serum creatinine above 35 μmol/L warrants further investigation for causes of renal dysfunction.[114]

Drug-drug interactions with antiretroviral agents

The metabolism of PIs, NNRTIs, maraviroc, cobicistat, elvitegravir and to some extent dolutegravir is through the CYP3A4 pathway of oxidative metabolism in the liver. These agents may have inducing or inhibiting effects on this metabolic pathway, and therefore have the potential to affect and be affected by the metabolism of other drugs. This interaction has a number of consequences, some advantageous and others potentially deleterious. In addition, there may be overlapping toxicities between agents which can be deleterious.

Advantages of drug-drug interactions between antiretroviral agents

As already discussed, the potent inhibition of the cytochrome p450 metabolic pathway by low dose ritonavir or cobicistat is used to boost the levels of a second PI or InSTI. This reduces the development of viral resistance and allows for twice daily, and in some cases once daily, dosing e.g. atazanavir/r, darunavir/r and elvitegravir/cobicistat

Disadvantages of drug-drug interactions between antiretroviral agents

  • Drug levels can be reduced and be inadequate for viral suppression, allowing viral resistance to develop e.g. dolutegravir and etravirine combined without the presence of a ritonavir-boosted PI will reduce dolutegravir exposure by 70-90%[115]
  • Overlapping toxicities e.g. hepatotoxicity with maraviroc and nevirapine

Drug interactions between antiretroviral agents and other drugs can be potentially life threatening. This potential threat is especially true of drugs that have a narrow therapeutic margin. Examples include the co-administration of PI/r or cobicistat, which must be avoided or used with extreme caution.

Other drugs with the potential for deleterious interactions either in a uni- or bi-directional manner include many of the anti-arrhythmic agents, oral anticoagulants e.g. warfarin, anti- psychotic and anti-depressant medication, blood pressure lowering medication, opiates, hormonal contraceptives and antimycobacterial agents i.e. clarithromycin and rifampicin.

It is essential to check the potential for drug-drug interactions and the need for dose adjustment when patients on concomitant medications are commenced on ART or patients on stable ART are commenced on other medications. Importantly dose adjustment may be indicated for the concomitant medications or the antiretrovirals themselves depending on the nature of the interaction. Further details are available in the DHHS guidelines[116] and from the University of Liverpool, UK, drug interaction website (www.hiv druginteractions.org). Seek expert advice if in doubt.

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