Antiretroviral treatment for HIV infection: Swedish recommendations 2019

Abstract

The Swedish Reference Group for Antiviral Therapy (RAV) published recommendations for the treatment of HIV infection in this journal most recently in 2017. An expert group under the guidance of RAV here provides updated recommendations. The most important updates in the present guidelines are the following: (a) The risk of HIV transmission through condomless sex from individuals with fully suppressed HIV viral load is effectively zero. (b) Pre-exposure prophylaxis (PrEP) is recommended for groups with a high risk of HIV infection. (c) Since the last update, two new substances have been registered: bictegravir and doravirine. (d) Dual treatment may be an alternative in selected patients, using lamivudine + dolutegravir or lamivudine + boosted darunavir/atazanavir. As with previous publications, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine. This document does not cover treatment of opportunistic infections and tumours.

Keywords:

• Antiretroviral
• HIV
• treatment guidelines
• Sweden
• adult
• paediatric

Introduction

HIV infection is a major global problem with increasing prevalence. UNAIDS estimates that approximately 37.9 million people were living with HIV in 2018, 1.7 million were newly infected and approximately 0.77 million died from AIDS-related illness. An estimated 23.3 million people were on antiretroviral treatment (ART) [1]. In total, an estimated 32 million people have died of the disease since the first cases of AIDS were described in 1981. According to the National Swedish Quality Registry for HIV (InfCare HIV November 2019), 8002 people living with HIV (PLHIV) (61% men, 39% women) were monitored and/or treated at the Swedish departments of infectious diseases and paediatrics in January 2019. One hundred and twenty of these were children and adolescents below the age of 18. The number of patients has increased by 3.1% during 2018. The main route of transmission was sexual; 51% heterosexual and 31% men who have sex with men (MSM), 5% of patients were infected through injecting drugs, 3% vertically from mother to child and 10% had an unknown transmission route or had been infected through infected blood products .

Antiretroviral medicines

Current antiretroviral medicines

HIV-drugs are categorized into six groups according to their antiretroviral activity into six groups (Table 1). Cross-resistance is not seldom seen within these groups, but not between groups. Virus entry into the cell can be inhibited by enfuvirtide (which blocks fusion by binding to the viral surface protein gp41), ibalizumab (a monoclonal anti-CD4-antibody that prevents HIV from infecting the cell – currently not available in Sweden) and maraviroc (binding to the cell’s CCR5-receptor thus preventing entry of CCR5-trophic virus). These medicines are rarely used. Nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcriptase (RT) (which synthesizes HIV DNA using HIV RNA as a template). Integrase inhibitors (INSTI) block the virus-specific enzyme integrase, thereby preventing viral DNA from being integrated into cellular DNA. Finally, protease inhibitors (PI) inhibit the viral protease and thereby the production of mature virus.

Table 1. Registered ARVs in Sweden including yearly cost (January 2019).

Generic name	Abbreviation	Brand name	Cost (360 d), USD^a
Nucleoside reverse transcriptase inhibitors (NRTI)
Abacavir	ABC	Ziagen	3111
Didanosine	ddI	Videx	*
Emtricitabine	FTC	Emtriva	2465
Lamivudine	3TC	Epivir, lamivudine^b	1664
Stavudine	d4T	Zerit	*
Tenofovir disoproxil fumarat	TDF	Viread, Tenofovir disoproxil^b	91
Tenofovir alafenamide	TAF	Vemlidy	5490
Zidovudine	AZT/ZDV	Retrovir	1679
Fixed combinations	ABC + 3TC	Kivexa, abacavir/lamivudine^b	1957
	TDF + FTC	Truvada, emtricitabine/tenofovir disoproxil fumarate^b	154
	TAF + FTC	Descovy	5654
	AZT + 3TC	Combivir, lamivudine/zidovudine^b	4387
	AZT + 3TC + ABC	Trizivir	7193
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Efavirenz	EFV	Stocrin/efavirenz^b	129
Nevirapine	NVP	Viramune, nevirapine^b	219
Etravirine	ETR	Intelence	4867
Rilpivirine	RPV	Edurant	3238
Doravirine	DOR	Pifeltro	4501
Fixed combinations	EFV + TDF + FTC	Efavirenz/emtricitabine/tenofovir disoproxil fumarate^b	398
	RPV + TDF + FTC	Eviplera	10,612
	RPV + TAF + FTC	Odefsey	10,099
	RPV + DTG	Juluca	9652
	DOR + TDF + 3TC	Delstrigo	9597
Protease inhibitors (PI)
Atazanavir	ATV	Reyataz	5665
Darunavir	DRV	Prezista, darunavir^b (800 mg × 1)	5515
		Prezista, darunavir^b (600 mg × 2)	8332
Fosamprenavir	fAPV	Telzir	4265
Indinavir	IDV	Crixivan	3743
Lopinavir fixed combination	LPV + RTV	Kaletra	5247
Ritonavir (100 mg × 1)	RTV	Norvir, ritonavir^b	397
Tipranavir	TPV	Aptivus	9678
Fixed combinations	ATV + cobicistat	Evotaz	5669
	DRV + cobicistat	Rezolsta	5910
	DRV + cobicistat + TAF + FTC	Symtuza	10,361
Integrase inhibitors (INSTI)
Dolutegravir	DTG	Tivicay	6399
Raltegravir	RAL	Isentress (400 mg 1 × 2 and 600 mg 2 × 1)	7059
Elvitegravir	EVG	Vitekta	*
Bictegravir	BIC + TAF + FTC	Biktarvy	11,651
Fixed combination	DTG + ABC + 3TC	Triumeq	11,353
	EVG + cobicistat + TDF + FTC	Stribild	12,527
	EVG + cobicistat + TAF + FTC	Genvoya	12,092
	DTG + RPV	Juluca	9651
Fusion inhibitors (FI)
Enfuvirtide	T-20	Fuzeon	19,226
CCR5-inhibitors
Maraviroc (150/300 mg × 2)	MVC	Celsentri (150/300 mg × 2)	10,979

^aThe Swedish pharmacy procurement price (‘AIP’) for standard adult doses (exchange rate as of 13 December 2012 where 1 USD = 9,38 SEK). The price of PI includes recommended dose of ritonavir. The first-line treatment in bold for comparison. For further information on the medicines, see SPCs or www.emea.europa.eu. *Not available in Sweden (January 2019).

^bAvailable as generic.

New substances

Since the previous update [2], several new drugs have become available as generics with significantly lower prices. Bictegravir (BIC) is a new integrase inhibitor available only as a combination tablet with tenofovir alafenamide (TAF) and emtricitabine (Biktarvy^®). BIC + TAF + emtricitabine (FTC) has been shown to be equivalent to dolutegravir (both in combination with abacavir (ABC) + lamivudine (3TC) and TAF + FTC) in terms of efficacy and side effects when given to treatment-naïve patients [3,4]. Doravirine is a new NNRTI available both as a single substance (Pifeltro^®) and in combination with TDF and 3TC (Delstrigo^®). Doravirine + TDF + 3TC fixed combination has been shown to be equivalent to efavirenz + TDF + FTC and doravirine as a single substance equivalent to darunavir/r (combined with 2 NRTIs) in the treatment of previously untreated patients [5,6]. A lower frequency of CNS side effects was seen compared to efavirenz. Darunavir/cobicistat (800/150 mg) is now available in fixed combination with TAF + FTC (Symtuza^®). Symtuza^® has been compared to darunavir/cobicistat + TDF/FTC when given to treatment-naïve patients, and as switch therapy in stable patients compared to patients remaining on boosted PIs + TDF/FTC [7,8]. The non-inferiority criteria were met in both studies. Juluca^® is a new fixed combination tablet of two previously available drugs, the INSIT dolutegravir and the NNRTI rilpivirine. This combination tablet has been shown to be similar in switch therapy compared to continued standard regimens in virally suppressed patients [9].

Generics and the financial aspect

Today there are, especially for treatment-naïve patients, a number of treatment alternatives with similar virological, immunological and clinical efficacy and with similar risk of side effects. The financial aspect should therefore be considered in the choice of first-line ART. As shown in Table 1, the cost varies considerably among different treatment combinations. TDF/FTC, ABC/3TC, TDF/FTC/efavirenz, efavirenz, nevirapine and darunavir are now available as generics.

A medicine available as a generic is often part of a fixed combination tablet where the other included substances have not reached generic status. Current scientific evidence does not support prescribing a fixed combination tablet at a higher cost than that of the same treatment divided into several components. At the population level, there is no convincing evidence that a single tablet once daily has better treatment outcomes compared to two or three tablets daily. On the contrary, a Canadian study found that switching to generics, and thereby more tablets, was not associated with a higher risk of treatment failure [10]. For example, Triumeq^® could easily be changed to Tivicay^® + generic TDF/FTC or for the more expensive alternative ABC/3TC if contraindications exist for TDF. Similarly, Odefsey^® and Eviplera^® should be exchanged for generic TDF/FTC + Edurant^® if no contraindications exist. Bictegravir is only available as a fixed combination with TAF/FTC and is, therefore, a significantly more expensive alternative than TDF/FTC + Tivicay^®. Doravirine should primarily be prescribed as Pifeltro^® + generic TDF/FTC as the combination tablet Delstrigo^® (TDF/3TC/DOR) is considerably more expensive.

Antiretroviral treatment

Preparations ahead of treatment

Good adherence to ART is crucial for long-term treatment success

Approximately one-third of HIV-1-infected patients that are diagnosed late in Sweden have an opportunistic infection or another AIDS defining complication [11]. In these cases, as in primary HIV infection and pregnancy ART should be initiated promptly (Section Antiretroviral treatment of primary HIV infection). For other patients, ART should be started as soon as possible. Prior to ART initiation a risk assessment regarding liver disease (including the presence of hepatitis B and/or C), cardiovascular disease, diabetes, renal disease, psychiatric illness, cognitive difficulties, drug and alcohol abuse, plans for pregnancy, etc. should be conducted (see Section Management of important adverse effects of antiretroviral therapy for details).

Patients should receive clear and individually adapted information about the importance of good compliance for good treatment results, both at treatment initiation and later during treatment. A pill organizer may be of value during treatment, especially during treatment initiation. Patients should also be informed of potential adverse drug reactions, dosage, and how to take the drugs.

When should treatment be initiated?

Recommendation

ART is recommended for all patients irrespective of CD4 counts. Postponed treatment initiation can be considered for patients with stable CD4 counts ≥500 cells/µl and non-detectable or very low viral load, including ‘elite controllers’.

Rationale for recommendation

There is international consensus that ART should be started as soon as possible, irrespective of CD4 counts. The risk of severe immunodeficiency related disease increases markedly at CD4 counts <200 cells/µl [12,13]. Even at CD4 counts 200–350 cells/µl the risk of AIDS defining and non-AIDS defining conditions increases compared to risk at higher CD4 counts [14–19]. The START study showed statistically significantly lower morbidity and mortality in patients starting ART with CD4 ≥ 500 compared to CD4 < 350. However, there is no evidence to support treatment initiation immediately at time of diagnosis in patients with normal CD4 counts and low viral loads [15]. There are also no data showing that treatment of ‘elite controllers’ is of clinical benefit.

Well-functioning ART eliminates the risk of HIV transmission through both heterosexual and homosexual relationships and probably by accidental needle sticks [20–22]. This is a very important reason for early treatment initiation.

The overall assessment of the expert group is that ART should in general be recommended to all PLHIV in Sweden. This recommendation corresponds to current treatment practices as 98% of all individuals diagnosed with HIV-1 in Sweden were on ART as of November 2019.

Choice of antiretroviral medicines in treatment naïve patients

Recommendation

Recommended first-line treatment in previously untreated patients:

• emtricitabine/tenofovir (TDF) generic + dolutegravir

• abacavir/lamivudine generic + ritonavir boosted darunavir (for women wishing to become pregnant)

Alternatively:

• abacavir/lamivudine generic or emtricitabine/tenofovir (TAF) + dolutegravir

• emtricitabine/tenofovir (TAF) + bictegravir

• emtricitabine/tenofovir (TDF) generic or abacavir/lamivudine generic + raltegravir (especially for women of fertile age where pregnancy is a possibility, during pregnancy raltegravir should be given twice daily)

• emtricitabine/tenofovir (TAF)/darunavir/cobicistat

• emtricitabine/tenofovir (TDF) generic or abacavir/lamivudine generic + efavirenz (women of fertile age where pregnancy is a possibility)

• emtricitabine/tenofovir (TDF) generic or abacavir/lamivudine generic + rilpivirine

• emtricitabine/tenofovir (TDF) generic or abacavir/lamivudine generic + doravirine

The recommended treatment regimens are considered equal concerning effect and safety. Apart from effect and safety, price and treatment of fertile women has been considered. In fertile women medicines with little experience in use during pregnancy (e.g. TAF, bictegravir, doravirine, etc.) should be used cautiously. A possible association between dolutegravir usage at conception and in early pregnancy and an increased risk of neural tube defects has been reported from a large study in Botswana [23]. Before more data is available dolutegravir should be considered not to be used by women who want to become pregnant. This also applies to bictegravir that is structurally similar to dolutegravir. However, women already using these drugs at the time of diagnosed pregnancy should be recommended to continue using a well-functioning treatment. Rilpivirine and cobicistat should be changed in pregnancy for pharmacokinetic reasons [24]. Raltegravir should be given twice daily (400 mg BID) during pregnancy. For further guidance on treatment of HIV in pregnancy we refer to the Swedish recommendations from 2017 [24].

Rationale for recommendation

Choosing NRTIs

The recommendation to include two NRTIs in first-line treatment remains. One of these should be lamivudine or emtricitabine. The recommended second NRTI is TDF because the generic fixed combination tablet with emtricitabine is significantly cheaper than other NRTI combinations. In case of contraindications for TDF or when a ritonavir- or cobicistat-boosted regimen is given, either generic abacavir/lamivudine or emtricitabine/TAF may be considered. Abacavir should not be used in HLA-B*5701 positive patients or in patients co-infected with hepatitis B. There are also data indicating slightly increased risk of cardiovascular disease with abacavir therapy [25,26]. These data are, however, contradicted by investigations unable to demonstrate an increased risk of cardiovascular disease [27]. As equivalent alternatives are usually available, abacavir is often avoided in patients at high risk of cardiovascular disease.

The difference between TDF and TAF can be summarized as follows: 300 mg TDF, containing the equivalent of 245 mg tenofovir, is converted to tenofovir in the systemic circulation and mainly excreted renally. Tenofovir exerts a dose-dependent toxicity on renal tubuli with an associated risk of osteoporosis. TAF remains unchanged after absorption and is eliminated through the bile. Elimination is fast with a half-life of 0.5 h. The alafenamide component is activated intracellularly by two known enzymes: catepsin-A, mainly available in polymorphonuclear leukocytes (PBMC), or CES-1 in liver cells. This particular pharmacology ensures high tenofovir concentration in the target cells. The intracellular concentration of active tenofovir (triphosphate) in PBMC is about four times higher with Genvoya^® (TAF 10 mg) compared to Stribild^® (TDF 300 mg). Systemic tenofovir exposure is a fraction of what is seen with TDF, which explains the lack of renal adverse effects. Therefore, TAF can be given to patients with decreased renal function. Alleged differences between TDF and TAF with respect to development of resistance have not been clinically documented.

Choice of third drug

Differences in virological effect between the three classes of drugs are considered clinically irrelevant in treatment naïve individuals [28–34], but there are other aspects to consider when choosing among INSTI, PI/r and NNRTI (resistance, adverse reactions, drug–drug interactions and cost).

Choosing INSTI

Dolutegravir, bictegravir, elvitegravir and raltegravir all have extensive documentation. Benefits of dolutegravir and bictegravir are a high barrier to resistance, few interactions and little effect on lipids, as well as once-daily dosing in patients who have not previously failed the first-generation INSTI. Bictegravir is only available in fixed combination with FTC/TAF and is more expensive than dolutegravir combined with FTC/TDF generics. Raltegravir has few interactions and is well tolerated with few side effects but has a low barrier to resistance. The virological efficacy of elvitegravir is similar to that of efavirenz and atazanavir as first-line treatment [35,36], but the barrier to resistance is low and the medicine also needs boosting.

Choosing PI/r

PIs should be boosted with ritonavir or cobicistat (PI/r or PI/c) [37]. The boosting increases the risk of drug–drug interactions. Darunavir/r or darunavir/c and atazanavir/r or atazanavir/c have not been compared directly in randomized controlled trials but are considered equivalent as treatment for naïve patients from an efficacy point of view. However, we recommend boosted darunavir as first-line treatment based on the following considerations:

Atazanavir has an increased risk of developing gall- and kidney stones over time [38,39] and icterus due to inhibition of the enzyme UGT1A is a common adverse effect. Another disadvantage of atazanavir is the decreased absorption seen in increasing pH, which means atazanavir should not be combined with proton pump inhibitors. Other aspects of effect and safety are considered equal for atazanavir and darunavir.

In treatment-naïve patients without resistant virus, other boosted PIs are considered equal to darunavir and atazanavir with respect to virological efficacy, but with more adverse effect. Other available PIs are therefore not recommended.

Choosing NNRTI

NNRTI are not suitable for patients with expected poor treatment compliance. Efavirenz is considered to have the best documentation and is, therefore, preferred over nevirapine and rilpivirine (recommendation grade B (Table 2)). Nevirapine can cause severe liver damage and severe hypersensitivity reactions, including Stevens–Johnson syndrome, and should therefore be avoided at CD4 cell counts <250/μl in women and 400/μl in men and in liver disease [40]. Efavirenz is associated with an increased risk of neuropsychiatric adverse effects (most commonly vertigo and vivid dreams), especially in the first 4–6 weeks of treatment and should be avoided in patients with psychiatric problems. The risk of resistance development after temporary treatment interruption is higher for efavirenz and nevirapine than other treatment regimes. Etravirine has not been studied in treatment-naïve patients and is, therefore, currently not recommended for this group. Rilpivirine is a well-tolerated alternative, but has a higher risk of treatment failure with development of resistance mutations, especially in patients with high viral load. Rilpivirine is mainly an option when switching drugs, e.g. due to side effects in patients with a satisfactory treatment response and with no previous treatment failure (see Section Switching treatment in PLHIV with viral suppression.), but can in some cases be used as an alternative in treatment-naïve patients with low viral load and expected good adherence. Rilpivirine should be taken with food and should not be combined with potent antacids (see Section Drug–drug interactions). NNRTIs are inappropriate for patients with expected poor compliance.

Table 2. Levels of evidence and recommendation (http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/).

Quality grading of evidence base

1a Systematic review (with homogeneity) of randomized controlled trials

1b Individual randomized controlled trials with narrow confidence intervals

1c ‘All or none’ all patients died before the treatment became available, but  some now survive on it; or when some patients died before the  treatment became available, but none now die on it

2a Systematic review (with homogeneity) of cohort studies

2b Individual cohort study (including low quality RCT; e.g. <80% follow-up)

2c ‘Outcomes’ Research; Ecological studies

3a Systematic review (with homogeneity) of case–control studies

3b Individual Case–Control Study

4 Case-series (and poor quality cohort and case–control studies)

5 Expert opinion without explicit critical appraisal, or based on physiology,  bench research or ‘first principles’

Grading of recommendations

A Based on evidence level 1a, b or c

B Based on evidence level 2a, b or c, 3a or b

C Based on evidence level 4

D Based on evidence level 5

Doravirine is a new NNRTI with less risk of neuropsychiatric side effects than efavirenz and also a higher barrier to resistance. It has shown promising results in phase III studies with non-inferiority after 48 weeks of treatment compared to efavirenz and darunavir/r [5,6]. Doravirine was approved in October 2018 and is not recommended as first line treatment due to lack of experience. Juluca^® is a new combination tablet containing an NNRTI (rilpivirine) and an INSTI (dolutegravir). The combination is an alternative in treatment switch when NRTIs cannot be given, e.g. due to side effects or isolated NRTI resistance. In the SWORD-1 and -2 studies, non-inferiority was shown compared to continued standard treatment (2 NRTI + INSTI/NNRTI/PI/r) 48 weeks after switching to dolutegravir/rilpivirine [9].

Combinations with only two active drugs

As mentioned, a fixed combination of dolutegravir and rilpivirine (Juluca^®) is now available. This combination may, in certain cases, be an alternative switch treatment for patients without NNRTI or INSTI resistance (known or suspected due to previous treatment failure). The restrictions for rilpivirine regarding concomitant treatment with acid inhibitors and adequate food intake must be considered. This, together with a relatively high price and so far limited experience, limits this treatment option.

Dolutegravir + 3TC demonstrated non-inferiority in the GEMINI-1 and GEMINI-2 trials compared to three drugs (dolutegravir + TDF/FTC) after 48 weeks of treatment of previously untreated patients without detectable drug resistance [41]. Previous studies have shown a high risk of development of resistance to INSTI in dolutegravir monotherapy [42,43], which is why it is of great importance that dolutegravir + 3TC is given to patients with no known prior virological failure or history of 3TC resistance. The working group’s assessment is that dolutegravir + 3TC is a conceivable new strategy, especially when switching in patients with already suppressed virus, but that this combination should be given with great caution until results from longer follow-up studies are available. So far, it is also a more expensive combination than dolutegravir + TDF/FTC treatment.

There is also data available showing effectiveness of dual therapy with darunavir/ritonavir + 3TC, a combination that in some cases may be relevant when switching treatment according to the same principles described above.

Treatment goals and monitoring

The virological treatment goal is to significantly reduce plasma HIV RNA after 4 weeks of treatment and to reach non-detectable levels within 3–6 months of treatment initiation (recommendation grade B). In patients with very high viral load it sometimes takes longer to reach non-detectable levels.

In a small proportion of patients with good adherence and appropriate treatment plasma HIV RNA can still be detected (at levels of 20–150 copies/mL) by current detection methods. If treatment and adherence are deemed fully appropriate, this low-level viremia (<150 copies/ml) does not necessarily equate treatment failure. In patients who show repeated measurements of viral loads >150 copies/ml after 6 months of treatment, failure should be suspected (see Section Management of treatment failure for management of treatment failure). Different quantification tests for HIV RNA can, especially when viral load is low, show different results. This means that a patient with previously undetectable viral load can be found to have low viremia when the test platform is changed.

Patients infected with resistant virus at diagnosis

Recommendation

• PI/r or INSTI (dolutegravir)-based regimens should be considered in patients infected with resistant virus even if the resistance pattern looks modest. When primary resistance mutations against PI or INSTI are present treatment must be adjusted accordingly.

Rationale

In recent years, infection with drug-resistant HIV has been observed in an increasing proportion of newly diagnosed patients in Sweden, 7.1% of newly diagnosed individuals in 2010–2014 compared to 5.6% in 2003–2010 [44]. Resistance mutations were most common among MSM (9.5%), but also among immigrants from sub-Saharan Africa (6.8%). During November 2017–September 2018, routine Sanger sequencing showed a 10% incidence of virus with resistance mutations when using the WHO list ‘Surveillance drug resistance mutations’ and 8.8% were considered potentially clinically significant (Emmi Andersson, personal communication).

Resistance is usually limited to one or two resistance mutations. The number of patients with NNRTI mutations has increased and is now at the same level as for NRTI resistance mutations. Transferred PI resistance is rare but has been described in nine cases in Sweden (2010–2014). From November 2017 to September 2018 no PI or INSTI mutations were found in a patient cohort based in Stockholm and Gothenburg. When treatment is initiated in patients with detected resistance mutations, it is important to remember that additional mutations may have been transferred but disappeared (reverted) after infection, which means that they cannot be detected in the resistance tests. A Swedish study shows that this does occur, but is rare (3/100 tested patients) [45]. This applies in particular to lamivudine/emtricitabine resistance (M184I/V mutation) and NNRTI resistance (mainly K103N and Y181C). A meta-analysis has shown that so-called minority virus strains (virus strains that constitute <20% of the virus population) can affect treatment outcome, especially for NNRTI-based treatment (see also Section Resistance testing) [46]. However, data suggest that if the resistant virus accounts for less than 5% of the virus population, the risk of treatment failure is not increased [47]. Further studies are needed to more accurately assess the relevance of resistance in smaller virus populations for different mutations and different medicines.

Tests for detection of resistance in minority strains are currently not available for routine use. PI/r or INSTI have a higher barrier to resistance than NNRTIs. For these reasons, PI/r- or INSTI-based treatment should be considered for first-line treatment in patients infected with resistant virus even when the resistance pattern looks modest. Renewed resistance testing should be performed when treatment response is worse than expected.

Continued treatment

Switching treatment in PLHIV with viral suppression

General considerations

A patient’s treatment should be regularly evaluated. Initial treatment should not just continue out of routine. The increasing availability of generics allows reduced treatment costs, which should be considered when choosing continued treatment.

When switching therapy in patients with a satisfactory treatment response, prior treatment history and resistance testing, as well as period of time without undetectable virus should be considered. If history and/or susceptibility testing indicates possible resistance to one or more drugs, new therapy should not contain these or cross-resistant drugs. Plasma HIV RNA should be measured 1 month after the treatment switch. If the viral load is then unchanged, subsequent follow-up visits and sampling can follow the normal sampling schedule (recommendation grade C).

Switching ‘old’ NRTIs

Zidovudine should only be used in rare circumstances where special conditions apply (see Section Lipoatrophy).

Treatment change because of adverse reactions

• Even if the patient has previously had a skin reaction to a drug in the NNRTI class, other NNRTI drugs can be considered as no cross-reactivity has been described for this adverse reaction.

• Switch from efavirenz to rilpivirine can be done when the above-mentioned criteria are fulfilled (recommendation grade A) [48].

• When switching to a maraviroc-containing regimen co-receptor assay should always be performed. If the patient has undetectable virus this test can be performed on PBMC or stored frozen plasma.

• When the entire NRTI class is contraindicated, there are a number of possible treatment combinations. In these cases, discussion with an HIV specialist is recommended (see Section InfCare HIV).

Treatment change to simplify treatment

The same advice applies as in (a), (b), and (c) above.

Management of treatment failure

• Treatment failure requires individualized management

Treatment failure is serious and should be dealt with in treatment conferences with experienced HIV specialists. Virological failure (for definition, see Treatment goals and monitoring) entails a risk of resistance development and progression of immunodeficiency and should be handled promptly. The risk of resistance progression in low-grade viremia is greater in patients who have prior drug resistance [49]. The most common cause of virological failure is inadequate adherence to medication.

Dealing with suspected treatment failure:

• Compliance and any changes in routines of the intake of medication should be carefully assessed.

• All of the patient’s medicines (ARVs and other medication, including any herbal remedies) should be reviewed so that interactions are not missed. E.g. many types of gastric acid inhibitors can be purchased without prescription and such co-administration results in significantly reduced absorption of atazanavir and rilpivirine. Medicines containing divalent cations, such as iron, multivitamin/mineral supplements, calcium substitution, antacids, may lower the concentrations of INSTI when taken concomitantly.

• Diets and other causes of malabsorption should be discussed.

• Therapeutic drug monitoring should be performed if the results are expected to affect patient management (see Section Therapeutic drug monitoring of ARVs).

• Genotypic resistance testing is strongly recommended, both at first-time failure (recommendation grade B) and repeated failure (recommendation grade A) [50]. At treatment failure, high-level resistance to efavirenz, nevirapine, lamivudine, emtricitabine, raltegravir, and elvitegravir can develop rapidly (within weeks). Measurable levels of viraemia during treatment with these drugs after a period of undetectable viral load (‘secondary treatment failure’) usually means that resistance to these drugs has developed. Resistance rarely develops during the first phase of treatment with decreasing viral RNA, but can develop if undetectable viral load is not achieved within six months (‘primary virological failure’).

Choice of therapy after treatment failure is individual and determined by treatment history, resistance patterns, cause of current treatment failure and adverse reactions. The treatment targets for treatment-naïve patients also hold for patients with failure of first-line treatment or with multiple treatment failures.

It has been well documented that two new active substances significantly improve treatment outcome compared to none or only one active substance; consequently, always aim for treatment to include at least two (and preferably three) active substances [51,52].

In patients with extensive resistance, individualized management and treatment are even more important. Zidovudine should, because of its toxicity, when possible, be avoided even in patients with previous virological failure [53]. For recommendations regarding treatment monitoring, see below.

Discontinuation of treatment

• Patients must be carefully informed about the risks of treatment discontinuation and advised against this. They should also be informed that the risk of transmission increases rapidly and markedly if treatment is stopped.

Treatment interruption has been shown to have adverse clinical, immunological, and virological long-term effects and it has also been associated with higher mortality (evidence level 1) [54]. If planned treatment interruption is done, the patient needs careful follow-up, as rapid decline in CD4 count is common. HIV RNA measurements should be performed as for untreated patients.

Treatment monitoring

Good adherence is the most important factor for successful treatment. Adherence should be discussed carefully before treatment initiation and then monitored and documented at every follow-up. In the InfCare HIV annual health survey the patients document their compliance (see below).

InfCare HIV

InfCare HIV is a clinical decision support tool, a research database, a national quality register, a health survey for ‘patient report outcome measures’ (PROM) and ‘patient report experience measures’ (PREM), and an application that allows for remote consultations with documentation of advice and planned follow-up. Biomarkers and patient-reported data are displayed graphically in the tool providing a clear picture of the patient’s HIV health condition. This is very valuable for both health professionals and patients. The software makes it possible to measure adherence to national treatment guidelines and has contributed to improved patient outcomes in Sweden.

InfCare HIV is committed to providing all PLHIV with an effective and equal care. Since 2008, all 29 clinics in Sweden that care for PLHIV are since 2008 part of the quality register and openly report their results to a national health care quality database.

At the national level, the proportion of PLHIV receiving ART increased from 72% to 98% between 2009 and November 2019. The register records four biomarkers and five patient-reported outcomes. Examples of these are viral load, where 95% of the treated patients achieved the target HIV RNA <50 copies/ml in 2019, and side effects, where 85% of the treated patients report not being affected by any adverse reactions in 2019. The InfCare HIV advisory board recommends that the health questionnaire is answered annually.

Laboratory monitoring

In patients with stable and well-functioning treatment monitoring twice yearly is sufficient, while more frequent monitoring may be warranted when there are concerns regarding resistance, adherence, etc. Resistance testing is recommended at diagnosis as well as at treatment failure (evidence level 2b, recommendation grade B). The recommended monitoring is summarized in Table 3.

Table 3. General laboratory monitoring.

New patients

Weight, length, blood pressure

HIV RNA, resistance markers, CD4 counts

RBC, WBC, PLT

S-Albumin, creatinine, estimated creatinine clearance, Na, K

Bilirubin, AST, ALT, ALP

Fasting B-glucose, triglycerides, cholesterol (incl. HDL, LDL)

U-albumin, U-erythrocytes, U-glucose

Syphilis serology, hepatitis serology (A + B + C)

STI-screening (offered to all patients), referral gynaecologist (women)

HLA-B*5701

Untreated patient (2–4 times/year)

Weight, blood pressure

HIV RNA, CD4 counts

RBC, WBC, PLT

Creatinine, estimated creatinine clearance, ALT, GT

STI-screening, incl. syphilis, at least once/year, offered to individuals at risk  of STI

HCV in PWID once/year and with increased liver function tests

Treated patient (2–4 times/year)

Weight, blood pressure

HIV RNA

CD4 counts (once/year enough in stable patients)

RBC, WBC, PLT

Creatinine, estimated creatinine clearance

ALT, bilirubin

Triglycerides, cholesterol, incl. HDL, LDL

STI-screening, incl. syphilis, at least once/year, offered to individuals at risk  of STI

HCV in PWID once/year and with increased liver function tests

Blood lipids (see above) is monitored the first year of new treatment  regimen, thereafter only if pathological results or if new treatment  is started

CD4 counts

The CD4 count provides a measure of the degree of immunodeficiency and in immunodeficient patients they should be followed 2–4 times/year until stable and normal levels are achieved. In stable patients monitoring once yearly is sufficient. The CD4 count is the most important indicator for the risk of developing opportunistic infections and tumours (evidence level 2a). CD4 counts are also used to complement plasma HIV RNA levels to evaluate the effect of treatment. Both the absolute count and percentage of CD4 cells are important for assessing the immunodeficiency and treatment effect. Usually, the absolute number and percentage correlate well. The percentage can be especially useful in situations with unexpectedly high or low absolute CD4 counts, where the suspected reason is unrelated to the HIV infection.

Plasma HIV RNA levels

The plasma HIV RNA level is the most important measure of the effect of HIV treatment. In untreated patients it gives some indication of disease activity, including how fast CD4 counts can be expected to decrease (evidence level 2a). Several commercial kits for the quantification of HIV RNA are available. These kits give similar results, but in the low range (between approximately 20–200 copies/mL) differences may sometimes be observed. All genetic subtypes within HIV-1 group M are quantifiable, but the tests are less reliable or not possible to use for HIV-1 group N, O, and P, and HIV-2.

Changes of >0.5 log units (approximately three-fold increase or decrease) are considered significant (evidence level 2a).

It is possible to measure HIV RNA in other body fluids, such as cerebrospinal fluid (CSF). This is warranted in some situations (see Section Antiretroviral therapy in late diagnosis of HIV infection). HIV DNA quantification is currently not used in routine care.

Resistance testing

Resistance testing is used for selecting effective drugs. Demonstration of resistance should be accompanied by an interpretation of the mutation pattern and an opportunity to discuss the results with a virologist as this has been shown to improve treatment outcomes (evidence level 2a, grade B recommendation). In Sweden, virus sequence data is electronically transferred to InfCare HIV to enable future re-analysis of the sequences against new antiretrovirals and when new knowledge about resistance becomes available.

Routine genotypic resistance testing identifies mutations in the protease and reverse transcriptase genes. The integrase gene (in INSTI therapy) and the envelope gene (in treatment with enfuvirtide or CCR5 inhibitors) can be investigated in treatment-naive patients and always in the event of failure on these drugs. The results are evaluated by the presence or absence of specific resistance mutations in these genes. For CCR5 inhibitors tropism for CCR5 or CXCR4 is assessed (see Section Tropism test). Mutations in PR and INSTI are divided into primary and secondary mutations. There are several web sites and consensus statements from expert groups in Europe and the United States that provide guidance for the interpretation of test results, including EuResist (http://engine.euresist.org), Stanford (http://hivdb.stanford.edu) and ANRS (http://www.medpocket.com/.). Sequences and clinical data can be entered on the EuResist site and this bioinformatic method then reports the 10 drug combinations that have the highest probability (with standard errors) to be efficacious. Both Stanford and EuResist are available through InfCare HIV and allow re-analysis of the stored InfCare HIV viral sequences.

Resistance assay should be performed during treatment or as soon as possible after treatment interruption because resistance mutations may disappear rapidly (within weeks) from the predominant plasma virus population if treatment is discontinued or changed, the so-called reversion (evidence level 2b). Plasma samples with <500–1000 HIV RNA copies/ml can sometimes be difficult to analyze with routine methods. The sensitivity can be enhanced by using the so-called nested primers in the PCR reaction. The lower limit for performing such a test is approximately 50 copies/ml even though resistance testing is not always successful at such low levels [55]. When an ultra-sensitive assay is required this must be specifically requested.

Tropism test

Before initiation of therapy with CCR5 inhibitors a tropism test must be performed. The test sequences parts of the viral envelope gene [56]. The sequence is then analyzed by the bioinformatics programme Geno2Pheno, which provides an assessment of whether the patient’s virus population uses the CCR5 co-receptor, the CXCR4 co-receptor or both (http://coreceptor.bioinf.mpi-inf.mpg.de). There is some uncertainty in the assessment and this is expressed as ‘false-positive rate’. The method has been developed primarily for subtype B. CCR5 inhibitors should not be used if all or part of the viral population uses the CXCR4 co-receptor. When a switch to a CCR5 inhibitor is considered for patients with low or undetectable viral loads, a sample with higher viral loads from before the last treatment can be used for tropism testing. Alternatively, DNA testing of mononuclear cells from peripheral blood can be considered.

Phenotypic tropism testing is available at commercial international laboratories, but is not recommended for routine use in Sweden or in the European guidelines [56].

Screening for cervical cancer

Recommendation

• HIV testing is recommended in women who have migrated from a high-endemic area with confirmed high cervical dysplasia and unknown HIV status (Table 4) (recommendation grade B).

• Women diagnosed with HIV should be referred for cervical cancer screening (HPV test and cytology) as soon as possible (recommendation grade B).

• Women living with HIV should be screened within the same age range as HIV-negative women, i.e. 23–64 years.

• Women living with HIV, older than 29 years with well-controlled HIV infection, negative HPV analysis and negative cytology at the first examination can be screened every 3 years. This also applies to the older screening ages 50–64 (Recommendation Grade B).

• Other HIV-infected women older than 29 years (positive oncogenic HPV test/abnormal cytology) should be screened every year. Women between 23 and 29 should be screened annually.

• Double testing with cell samples for HPV and cytology should be done in women living with HIV (as in HIV negative) at about 40 years of age

Table 4. Indicator illnesses.

STI; chlamydia, gonorrhoea, syphilis, genital ulcers, lymphogranuloma venereum

Tuberculosis

Lymphoma (all types)

Cervical and anal cancer/high-grade dysplasia

Herpes zoster at age <65 years

Hepatitis B and C, acute or chronic

Mononucleosis-like symptoms and non-specific lymphadenopathy

Anaemia, thrombocytopenia, and leucopoenia with duration of more than four weeks

Seborrhoic dermatitis / oral candidiasis

Rationale

Women living with HIV have an increased risk of persistent infections with oncogenic human papilloma virus (HPV) and an increased risk of developing cervical cancer [57,58]. Women living with HIV in Sweden have a more than nine-fold increased risk of high-grade cervical dysplasia (cervical intraepithelial neoplasia grade 2 or worse [HSIL/CIN2+]) [59]. Access to effective ART and retained immune system (CD4 > 500 cells/µl) is associated with a reduced risk of dysplasia and better outcomes after treatment (conization) of these [60,61]. Women who live with HIV and have normal cytology tests as well as negative HPV tests show the same low risk as HIV-negative women to develop severe dysplasia, regardless of CD4 level, after 5 years of follow-up [62]. In contrast, women who live with HIV with normal cytology tests but who test positive for HPV16 have been shown to have a higher risk of developing severe dysplasia than HIV-negative women [63]. Long-term follow-up has shown that women living with HIV who are compliant with cervical cancer screening have a low risk of cervical cancer corresponding to that of HIV-negative women [64,65]. In light of the above, recommendations for cervical cancer screening of women living with HIV have been adjusted in national and international guidelines in recent years and are now more comparable to those for HIV negative women including triaging with HPV testing [66–68]. High-grade dysplasia is classified as an indicator disease for HIV and women with unknown HIV status who have migrated to a low-endemic from a high-endemic country should be tested for HIV in connection with the diagnosis of HSIL/CIN2 + [69].

Screening for anal cancer

Recommendation

There is currently no scientific evidence or practical possibility of introducing cytology or HPV based screening for anal cancer. However, regular anal palpation or proctoscopy can be a way of early detection of anal cancer.

Rationale

In Sweden, a few hundred cases of anal cancer are diagnosed annually, of which some lead to persisting illness or death. These cases are almost exclusively caused by HPV, mainly HPV-16 or HPV-18 [70]. Among MSM the prevalence of HPV infection is high and is seen in almost all PLHIV. Estimates from the UK and the USA have shown that prevalence of anal cancer is 5–10 times higher among MSM living with HIV and comparable to the prevalence of cervical cancer in women before cervical screening was introduced [71]. Improved immune status could have contributed to the reduced development of anal cancer although it should be recalled that prolonged survival provides more time to potentially develop the cancer. While communities wait for HPV vaccines to be introduced for males and for such vaccination programmes to have effect, screening for anal cancer has started in Amsterdam, New York, and Barcelona, among others.

Due to a consistent occurrence among MSM, HPV assay cannot be used as screening for anal cancer. However, cytology can detect different degrees of cellular dysplasia in the majority of examined individuals. Both specificity and sensitivity are considered lower than for cervical cancer. In cases of cellular dysplasia further examination with high-resolution analoscopy (HRA) can be performed. This allows targeted biopsies and local treatment in early stages of disease. HRA is resource intensive and in Sweden there is currently a shortage of trained users.

Treatment in special situations

Post-exposure prophylaxis

Recommendation

Post-exposure prophylaxis (PEP) may be indicated after incidents where HIV contaminated instruments have penetrated the skin (evidence level 3b, recommendation grade B), after unprotected sex with an untreated or sub optimally treated PLHIV, or after sharing a syringe with an HIV infected person who injects drugs (evidence level 5, recommendation grade D). PEP may also in some cases be indicated after exposure of mucous membranes or broken skin to HIV-infected blood (recommendation grade D). PEP is not usually recommended when the HIV status of the index person is unknown.

Rationale

The risk of infection after injection incidents or broken condoms is very small if the index patient is on ART with stable undetectable HIV RNA. In the case of condom failure (irrespective of type of intercourse), the risk of infection can be considered non-existent if the index patient is on ART and has stable non-detectable HIV RNA. Data from the PARTNER study has shown no transmission of sexual exposure from a person on ART and plasma HIV RNA <200 copies/ml [22]. PEP is therefore not recommended if it can be confirmed that the index case is on effective ART. If this cannot be ascertained in the acute situation, it is recommended to initiate PEP and reconsider therapy when information becomes available.

When applicable, PEP should be started immediately, regardless the time of day. When more than 36 h have elapsed, there is no indication for PEP (evidence level 3b, recommendation grade B). Consultation with a physician experienced in HIV treatment is recommended as soon as possible, but the initiation of prophylaxis should not be delayed pending such consultation.

Treatment with emtricitabine/tenofovir (200/245 mg 1 × 1) + raltegravir (600 mg 2 × 1) is given for four weeks (recommendation grade D). If the index patient’s virus has known resistance to these medicines other treatment combination may be more suitable, and PEP should then be adjusted to the resistance pattern and treatment history of the index patient. Scientific evidence for choice and duration of PEP is poor [72].

Time to initiation of treatment is the most important factor for the success of PEP and in the absence of the recommended PEP drugs, or when there is uncertainty about the most appropriate regimen, another available drug combination should be given. Abacavir and nevirapine should be avoided due to the risk of severe hypersensitivity reactions.

When PEP is given, the exposed person should be tested with serological test (Combo EIA) at least on day 0 and 6 weeks after treatment has been completed. When PEP is not given but the assessment is that there was a real risk of exposure, it is recommended to sample the exposed person at the time of seeking care as well as 6 weeks after exposure [73] (evidence level 5). Additional earlier sampling should be performed if the patient develops symptoms suggestive of primary HIV infection. Immediate start of ART should then be considered. Rapid tests are slightly less sensitivity and should not be used in this circumstance. The reason for extending the follow-up to 6 weeks after completed PEP is that antibody development most probably is slower when infection occurs despite PEP. Psychological support is of great importance during the entire follow-up period, but especially during the first four weeks as these are associated with the greatest risk of psychological problems and termination of treatment.

Pre-exposure prophylaxis

Recommendation

Pre-exposure prophylaxis (PrEP) is recommended to high-risk individuals.

Background for recommendation

PrEP involves the administration of antiretroviral drugs prophylactically to persons who are at high risk of contracting HIV. PrEP is most extensively used in the USA where FTC/TDF has been registered for this indication since 2012, but in the last year, the use has increased rapidly even in Europe. Apart from protecting the individual, PrEP is used as a strategy to halt the HIV epidemic. An Australian study has shown decreased transmission among MSM after introduction of PrEP [74]. Available studies indicate that FTC/TDF is effective as PrEP as long as the drug is taken as recommended. In studies persons who have become infected have usually not taken their medication. In Europe, two pivotal studies with different study designs show high protective effect of PrEP in MSM; In a British study (PROUD) one FTC/TDF tablet was given daily and in a French study (IPERGAY) the drug was instead taken on demand, i.e. two pills 2–24 h before sex and thereafter one pill daily for 2 d after the last sexual encounter. In both studies an 86% reduction in HIV transmission was observed [75,76]. Using PrEP for certain high-risk groups, e.g. MSM and transgender persons, is recommended by the European AIDS clinical society (EACS), the Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO) [77].

However, provision of PrEP is not entirely uncomplicated. First, high-risk individuals need to be identified. Partners of known PLHIV are rarely considered high risk because almost all PLHIV in Sweden are on effective ART and the risk of transmission is therefore minimal. HIV transmission is most common among MSM. However, the number of new infections has decreased in the last years and therefore a limited number of transmissions could have been prevented by PrEP. PrEP should rather be seen as a way of protecting individuals with very high-risk sexual behaviour. Transmission still occurs abroad during sexual encounters. Among individuals engaging in such behaviour PrEP may be an option.

Before initiating PrEP, the absence of HIV infection has to be ensured. If not, resistance may develop against essential antiretroviral drugs. FTC/TDF is also active against hepatitis B virus and serological testing for chronic hepatitis B should be performed. The treatment can also cause adverse effects and follow up of this should be done, at least if PrEP is provided during longer time periods. There is also a risk that PrEP may give a false sense of protection leading to compensational risk behaviour and increased risk of other sexually transmitted infections. It is, therefore, important to discuss risk minimisation of sexual transmission. In summary, PrEP requires careful consideration and an implemented strategy with respect to the choice of participants, testing and follow-up.

The Swedish council for new therapies (‘NT rådet’) presented their recommendations in June 2018. They are based on the previous recommendation from the Public Health Authority and RAV (https://www.sls.se/rav/rekommentions/HIV/preexpositionsprofylax2017/).

The recommendations imply that FTC/TDF can be given preventively to individuals in certain risk groups, primarily MSM, and that the prescription is then covered by the social security. PrEP should be prescribed at clinics with experience in HIV treatment, preferably in collaboration with an STI clinic. PrEP should be available as soon as possible in all health care regions.

Antiretroviral treatment and risk of transmission

A position statement on the risk of HIV transmission during ART has been published [78] and is here summarized:

There is a strong correlation between plasma viral load and the risk of HIV transmission. This has mainly been studied for vaginal intercourse, e.g. in the HPTN 052 study [19]. The PARTNER study is an observational study focussing on the risk of sexual transmission (condomless sexual intercourse) when a PLHIV is on treatment. In the interim analysis of 1100 couples (of which 40% were MSM) no transmissions could be seen from PLHIV on effective ART [79]. The second phase of the study, PARTNER 2, included serodiscordant MSM couples (one partner HIV-infected and the other HIV-negative). To be included in PARTNER 2, the HIV-infected person must be on ART and not use a condom regularly. The study followed nearly 1000 MSM serodiscordant couples from 14 different countries in Europe from September 2010 to April 2018 with 77,000 reported events of condomless anal sex without any HIV transmission occurring. The results underline the importance of early diagnosis and treatment [22]. In the slightly smaller study ‘Opposite attract’ that included serodiscordant MSM couples from Australia, Thailand and Brazil, no HIV transmissions were observed in approximately 17,000 episodes of condomless sex [21]. The non-existent risk of sexual transmission in well-treated HIV is also supported by the fact that no such cases have been documented [80].

The risk of sexual transmission is therefore negligible for vaginal and anal intercourse if the HIV infected individual fulfils the criteria for effective ART, defined as plasma HIV RNA <50 copies/mL on two occasions at 6 months interval, presumed good treatment adherence and follow up of viral load 2–4 times per year [81]. Effective ART is also expected to decrease the risk of transmission between people sharing injection tools. The risk of perinatal transmission from mother to child is very low when effective ART is initiated in time before the delivery.

Because effective ART leads to an eliminated risk of transmission this influences decisions about starting therapy and PEP. It also means that discordant couples can choose natural conception if they want children as long as the HIV infected partner has effective ART. Such a decision needs to be thoroughly discussed with the physician treating the patient. An effectively treated PLHIV may choose to have unprotected sex without risking infecting his or her sexual partner. Condom coercion in these cases has no support in science and proven experience but should still be recommended to prevent transmission of other STIs.

Antiretroviral treatment of primary HIV infection

There are no reliable long-term data regarding potential clinical, virological and immunological advantages of early ART in individuals with primary HIV infection (PHI), but data suggest potential benefits of starting ART early during PHI. These benefits include reduced HIV-associated morbidity [82,83], preservation of HIV-specific immune response [84], slower disease progression [85–87], smaller virus reservoir [88], especially in the central nervous system [89], and reduced HIV transmission. The Working Group therefore recommends:

• All patients with confirmed PHI should be offered ART immediately (recommendation grade B).

• Patients with clinically suspected PHI should be offered ART while diagnosis is being confirmed or rejected.

No data exist regarding whether ART initiated for PHI should continue without interruption. However, increased mortality has been observed in chronic HIV infection in patients randomized to planned treatment interruptions compared to patients randomized to continuous therapy [54]. We, therefore, recommend continuing ART as in chronic HIV infection even in individuals who have started ART because of PHI.

In other aspects, the principles for treatment of chronic HIV and PHI are the same (the choice of ART, resistance testing prior to initiation of therapy, virological and immunological targets, monitoring, etc.). In PHI, one should not wait for the determination of viral resistance patterns but treatment should be initiated immediately as mentioned above. If any resistance is detected, the treatment can be modified later.

Antiretroviral therapy in late diagnosis of HIV infection

Patients with low CD4 counts (<350 cells/µl) at diagnosis should start ART as soon as their clinical and psychosocial state allows it. There are reports of patients seeking care with HIV associated symptoms without being tested for HIV. It is recommended to test patients who seek care with symptoms of the so-called indicator diseases (Table 4). These diseases have an expected HIV prevalence >0.1% in a European population (www.hiveurope.eu). In Sweden, tuberculosis is an additional indicator disease [90].

Antiretroviral therapy for HIV-associated dementia

HIV-associated dementia is nowadays very rare and almost exclusively affects patients without ART. Less severe HIV-associated neurocognitive impairment can occur even in patients who are on treatment, but it is not known to what extent. For the definition and diagnosis of HIV associated neurocognitive impairment, see International recommendations [91].

It is important to determine the cause of neurocognitive impairment as the management depends on the underlying cause. The investigation should include neurological examination and possibly neuropsychological testing to more reliably assess the presence and degree of neurocognitive impairment. There is no evidence to support neuropsychological screening of patients without neurological or neurocognitive symptoms. Quantification of HIV RNA in CSF is important to differentiate between HIV associated disease and other causes, particularly in patients on ART. In treated patients, symptoms are unlikely caused by HIV if CSF HIV RNA is <50 copies/ml. Analysis of other markers (inflammatory and cerebral injury) could be done for differential diagnosis. Brain imaging, primarily with magnetic resonance imaging is part of the assessment, primarily to rule out other causes of the symptoms.

For many antiretrovirals, there are little data regarding CNS penetration. The following are suggestions for treatment of patients with HIV-associated dementia (patients with less severe neurocognitive impairment are recommended standard treatment, see Section Recommendation):

• Patients without ART: if fully sensitive virus, start ART with at least two antiretroviral medicines that have good penetration into the CNS. Consult HIV specialist.

• Patient already on ART: if virological failure in plasma, the ART should primarily be adjusted to cope with this (see Section Management of treatment failure). If, however, HIV RNA <50 copies/ml in plasma, but >50 copies/ml in CSF, genotypic resistance testing of virus in CSF should be performed when possible, and treatment revised taking into account possible resistance and CNS penetration (see above) (Recommendation grade C).

Antiretroviral treatment of HIV-2 infection

All HIV-2 treatment should be discussed with an HIV specialist with experience of such treatment.

• Immunodeficiency usually develops slower in HIV-2 than in HIV-1 infection, but the inter-individual variation is considerable. In patients with stable CD4 counts >500 cells/µl and low viral load treatment initiation can be postponed.

• It is recommended to start treatment at (according to the French treatment guidelines, 2016) [92]:

• Clinical symptoms of immunodeficiency

• CD4 counts ≤500 cells/µl

• Decrease in CD4 count of ≥30 cells/year

• Repeated detectable hiv-2 plasma RNA

• Age above 40 years

• Comorbidity with HBV, HCV, or tuberculosis

French guidelines strongly recommend resistance testing for protease, RT and integrase before starting treatment as primary resistance greatly impairs the patient’s treatment possibilities.

When treatment is given several specific aspects need to be considered. CD4 count recovery is reported to be slower and less complete in the treatment of HIV-2 than HIV-1 and clinical experience shows that treatment failure is more common in HIV-2 infection than in HIV-1 infection. For treatment naïve HIV-2 patients the first-line recommendation is FTC/TDF or ABC/3TC + dolutegravir. Dolutegravir data are mainly based on in vitro evaluations and it is, therefore, recommended to be taken twice daily.

In case of treatment failure on the first-line therapy, treatment options are very limited. DRV/r is recommended when DTG is used as the first-line treatment and DTG when DRV/r is used as the first-line treatment.

Good compliance is even more important in the treatment of HIV-2 infection than HIV-1 infection because the options for the second-line treatment are limited and because the genetic barrier to resistance probably is lower than for HIV-1.

Knowledge of how HIV-2 should be treated is limited and there are no large clinical studies. These recommendations are mainly based on small cohort and clinical case studies [93]. In principle, the present guidelines follow the French and European recommendations for the treatment of HIV-2 infection from 2016 and 2017 [93].

All NRTIs appear to have clinically relevant activity against HIV-2. However, the genetic barrier to resistance seems to be lower than for HIV-1 because the K65R and Q151M multi-resistance mutations seem to develop more easily, especially during treatment with zidovudine and other ‘older’ NRTIs [93]. Tenofovir or abacavir resistance is conferred by the same mutations as for HIV-1. All NNRTIs lack activity against HIV-2. Among PIs darunavir, lopinavir and saquinavir have clinically relevant activity against HIV-2, while the other PIs seem to have limited effect. The genetic barrier against PI resistance has been reported to be lower than in HIV-1 infection. The INSTIs dolutegravir, raltegravir and elvitegravir appear to have clinically significant activity against HIV-2 although in vivo data are very limited. Enfuvirtide lacks activity against HIV-2. Available data indicate that maraviroc can inhibit HIV-2 strains using CCR5.

Knowledge of how to interpret results from HIV-2 resistance testing is incomplete, although two algorithms for interpretation (EU-HIV-2 and Rega) are available on the HIV-GRADE website (https://www.hiv-grade.de/cms/grade/homepage/). Co-receptor tropism can be determined.

Dosing ART in reduced renal function/dialysis or reduced liver function

Data regarding ART in individuals with reduced renal and/or liver function are limited. These patients should be followed carefully regarding treatment effect and adverse effects, and therapeutic drug monitoring should be performed liberally.

PIs, NNRTIs and INSTIs do not need dose adjustment in PLHIV with reduced renal function, but dose adjustment is recommended for all NRTI except abacavir and TAF. See respective SPCs for details.

Dosing of ARVs in intermittent haemodialysis and continuous hemofiltration is described by the Department of Health and Human Services (DHHS): https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/44/arv-dosing-for-renal-or-hepatic-insufficiency.

Patients with reduced liver function due to chronic hepatitis have increased risk of serious hepatotoxic adverse reactions [94,95] and these patients should be followed carefully when initiating new ART.

There are no data to support use of boosted PIs and NNRTIs in patients with severe liver disease (Child-Pugh B and C). Additionally, there are no data regarding use of dolutegravir, raltegravir and elvitegravir/c in patients with Child-Pugh C. As for other medicines care should be taken when used in patients with liver disease. Therapeutic drug monitoring can help determining treatment dose of boosted PI in patients with moderate to severe liver disease. If a serious treatment induced adverse liver reaction is seen, termination of treatment should always be considered. When treatment is restarted a new combination should, if possible, be used (recommendation grade D).

Treatment in co-infected patients

Antiretroviral treatment with hepatitis B or hepatitis C co-infection

Co-infection with HIV and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is relatively common as a result of similar transmission routes. In Sweden, 4% of PLHIV are co-infected with chronic HBV (HBsAg positive) and 7% with HCV (HCV RNA positive), with a higher prevalence (50–90%) in certain groups, such as people who inject drugs (PWID) and haemophiliacs (InfCare HIV November 2018). The rate of progression of liver damage in patients with hepatitis is faster in individuals with HIV infection compared with patients without HIV [96] and, thus, liver complications have become a leading cause of morbidity and mortality in co-infected patients in parts of Europe [97]. Early treatment initiation is important for PLHIV co-infected with HBV and/or HCV as immune reconstitution and viral inhibition leads to slower development of liver fibrosis.

Co-infection with hepatitis C:

• Selection of HCV treatment in HIV co-infected patients should follow the same principles as for HCV mono-infected patients. The treatment outcome in co-infected individuals with interferon-free direct-acting regimens has consistently been as good as for HCV-mono-infected individuals [98].

• Consider drug-drug interactions (updated drug interactions at www.hiv-druginteractions.org). For some individuals, HIV treatment may need to be adjusted due to interactions. This should be done well in advance of starting HCV treatment. There are interactions between the interferon-free direct-acting HCV drugs and most protease inhibitors as well as NNRTIs. Integrator inhibitor-based ART can be given together with all HCV regimens.

• Patients with ongoing ART should have stable treatment with non-detectable plasma HIV RNA. Details can be found in the updated recommendations for treatment of HCV [98].

Co-infection with hepatitis B:

• The first choice of treatment should be effective against both HIV and HBV for any patient who needs treatment for either infection. Tenofovir, lamivudine and emtricitabine have clinically relevant activity against both HBV and HIV. Entecavir has a weak effect against HIV, which can lead to the development of resistance to HIV drugs when treatment is given against HBV to co-infected patients without effective HIV treatment. In practice, this means that tenofovir (TDF or TAF)/emtricitabine should be included as part of ART as long as there are no contraindications.

Vaccination against hepatitis a and B:

MSM and PWID living with HIV and who are not immune against hepatitis A and B should be vaccinated against these infections. In patients with severe immunosuppression, additional doses may be needed to achieve protective anti-HBs levels [99]. One option is to vaccinate after CD4 counts have increased after ART initiation. In PLHIV with CD4 > 500/µL the vaccine response is similar to that of HIV negative individuals.

Antiretroviral therapy in tuberculosis and other mycobacterial co-infections

Active tuberculosis

Treatment of active tuberculosis in PLHIV follows the same principles as for HIV negative individuals regarding medicine of choice, treatment duration and follow-up. Concomitant treatment of both infections requires good compliance and there is a risk of drug–drug interactions, overlapping adverse effects, and immune reconstitution inflammatory syndrome (IRIS).

In treatment-naïve patients, tuberculosis treatment should be started first, and ART should be started as soon as clinically possible (evidence level 1a). This means as soon as possible within two weeks for patients with CD4 < 50 and as soon as possible within eight weeks for other patients. In patients with tuberculosis meningitis, there is uncertainty about the optimal timing of ART initiation. As for cryptococcal meningitis (Section Screening for tuberculosis and treatment of latent tuberculosis), it may be good to postpone treatment by 4–8 weeks after starting tuberculosis therapy to reduce the risk of IRIS.

Medicines against mycobacteria should be selected and dosed in view of the risk of interaction with antiretroviral drugs. Rifamycins (rifampicin or rifabutin) are an important basic component of tuberculosis treatment, but they interact with several medicines from different groups of ARVs. Some basic recommendations for suitable combinations are given below. Use http://www.hiv-druginteractions.org/ or www.hep-druginteractions.org to check for possible interactions.

Recommendations for co-treatment of HIV and tuberculosis:

• efavirenz regular dose (600 mg × 1) + two NRTIs and isoniazid, rifampicin, ethambutol and pyrazinamide in regular doses

or

• dolutegravir regular dose + two NRTI and tuberculostatics as above, with the difference that rifabutin dosed 300 mg daily replaces rifampicin. An alternative is to give dolutegravir 50 mg × 2 with isoniazid, rifampicin, ethambutol, and pyrazinamide in regular doses

or

• The combination of PI/r and rifampicin is contraindicated. Instead, use PI/r in normal dosage + two NRTIs with rifabutin, isoniazid, ethambutol and pyrazinamide. The optimal dose of rifabutin with PI/r is not clear and may vary with different PIs. For the most commonly used PI, darunavir/r, there are limited data indicating that rifabutin 150 mg/day is the most appropriate dose [100]. Follow-up monitoring of the drug concentration of rifabutin is recommended. Be aware of side effects such as neutropenia and uveitis.

TAF is not recommended in combination with any of the above mentioned rifamycins because concentrations of TAF may be too low as it is a substrate of P-glycoprotein induced by the rifamycins. Cobicistat, rilpivirine and doravirine are contraindicated in combination with rifampicin and are also not recommended with rifabutin because the concentrations of the two drugs become too low. Bictegravir is only co-formulated with FTC/TAF, and is contraindicated in combination with rifampicin and is also not recommended in combination with rifabutin due to greatly reduced concentrations (even when given in double dose) [101].

Co-treatment of infection with HIV and atypical mycobacteria (MAC)

Recommended treatment of MAC is clarithromycin 500 mg × 2 and ethambutol 15 mg/kg × 1 with an optional addition of rifabutin 300 mg × 1. Clarithromycin can be replaced by azithromycin if needed because of adverse reactions or drug–drug interactions. Note that efavirenz and boosted PI (and Genvoya) interact with macrolides and rifabutin. The following treatment combinations are recommended:

• MAC-treatment as above (no dose adjustment needed) with dolutegravir (or raltegravir) + 2 NRTI

or

• MAC-treatment as above with rifabutin 450 mg × 1 with efavirenz in normal dose + 2 NRTI

or

• PI/r usual dose + 2NRTI with rifabutin 150 mg/day (and clarithromycin and ethambutol as above).

Screening for tuberculosis and treatment of latent tuberculosis

Recommendation

• General screening or treatment of latent TB in PLHIV is not recommended.

Background

Globally, TB is the most important HIV-associated opportunistic infection. The risk of developing active tuberculosis for a person with untreated HIV and latent tuberculosis is about 10% per year. The risk is greatly reduced for people on ART, but PLHIV continue to have about twice the risk of developing active tuberculosis compared to HIV-negative individuals. Of an estimated 10.4 million cases of tuberculosis in the world in 2015, 1.2 million (11%) are estimated to have been in PLHIV [102]. In Sweden, a total of 506 cases of tuberculosis were reported in 2018, of which 428 (85%) are estimated to be infected abroad [103]. It is unknown how many of these people have concomitant HIV infection.

The majority of PLHIV diagnosed with tuberculosis in low-incidence countries are diagnosed at the time of HIV diagnosis [104,105], but development of active tuberculosis also occurs in individuals on ART. In a Swedish observational study of 1868 PLHIV, 92 developed tuberculosis, of which 24 (26%) were diagnosed with tuberculosis at least one year after being diagnosed with HIV [106]. However, it is not clear how many of these had HIV RNA <50 copies/ml.

In addition to starting ART, the risk of progression of latent to active tuberculosis in PLHIV can also be reduced with preventive tuberculosis treatment. Prophylaxis against latent tuberculosis with izoniazid monotherapy is recommended to all PLHIVs in resource-strained countries. In a study from South Africa on PLHIV on ART, prophylactic treatment with isoniazid reduced the risk of active tuberculosis by 37% compared to placebo [107]. The protective effect of the prophylactic treatment lasted for the entire 7-year follow-up period in a study from Brazil (medium tuberculosis incidence) among PLHIV [108]. Corresponding studies using ‘modern’ ART in high-income countries are not available.

The clinical picture of tuberculosis in PLHIV with immunosuppression is often atypical and classical symptoms are often not present in certain individuals. In PLHIV with subclinical active tuberculosis may become clinically manifest when ART is initiated and the immune system is strengthened. This is sometimes called ‘unmasking’ and is a form of IRIS.

General screening for latent tuberculosis is not recommended, neither is treatment for latent tuberculosis in PLHIV. These recommendations are based on current experience in Sweden, where we have failed to identify reactivated tuberculosis as a problem. In Sweden, we have regular clinical follow-up of PLHIV, ensuring possibility for early diagnosis of active TB. This is particularly important in patients with severe immunosuppression where extrapulmonary tuberculosis and atypical manifestations of pulmonary tuberculosis are common.

When to start antiretroviral therapy against opportunistic infections (other than TB)

Recommendation

• Start ART as soon as the patient’s clinical condition allows.

• In cryptococcal meningitis, ART initiation should be postponed by 4–8 weeks.

Background

One advantage of initiating ART early is to avoid further deterioration of the patient’s immune system. The disadvantage of early treatment may be drug interactions, overlapping toxicities, and increased risk of IRIS. In opportunistic infections where specific therapy is not available (e.g. progressive multifocal leucoencephalopathy (PML), cryptosporidium infection, and microsporidiosis) ART should be started as soon as possible as this will improve the outcome by improving the immune response (recommendation grade A). Even in Pneumocystis jiroveci pneumonia (PCP) early initiation of ART is associated with improved survival and should be started as soon as possible (recommendation grade A) [12].

The optimal time for initiation of ART in patients with cryptococcal meningitis has not been determined. A small randomized study of 35 patients from the USA and South Africa with cryptococcal meningitis found it safe to start ART within 14 days of starting treatment against cryptococcal meningitis [12]. Two other larger randomized studies from Uganda, Zimbabwe and South Africa found increased mortality when ART was initiated early compared to later initiation of treatment [109–111]. Early treatment in these studies was 72 h or 1–2 weeks, late initiation was 10 or 5 weeks. Furthermore, the ART was different to the one used in Sweden, which makes the results difficult to apply to Swedish conditions. Based on available data it seems appropriate to postpone the start of treatment by 4–8 weeks, especially in patients with increased intracranial pressure or low levels/no CSF pleocytosis (recommendation grade D).

Prophylaxis against opportunistic infections

Primary prophylaxis against opportunistic infections is usually only given for PCP. However, trimethoprim-sulphamethoxazole, which is the recommended first line prophylactic agent, also has an effect on other opportunistic infections, such as toxoplasmosis and respiratory tract infections. Primary prophylaxis against PCP is generally recommended at CD4 counts <200 cells/µl.

Primary and secondary prophylaxis against PCP can usually be terminated when effective ART has resulted in undetectable virus loads at repeated measurements at least 3 months apart [112].

Vaccination

Individuals who have not been immunized according to the paediatric vaccination schedule should be offered these vaccinations (recommendation grade A). Travel vaccines, including yellow fever, can be given in the same way as for HIV negative individuals – with certain exceptions (see below) (recommendation grade D). Consider measuring antibody titres after vaccination as boosters are sometimes needed (e.g. hepatitis B) (recommendation grade D).

Immunization with inactivated vaccines

• Inactivated vaccines can be given irrespective of immune status (recommendation grade B)

• Influenza vaccine (inactivated) should be offered as for HIV-negative individuals (recommendation grade B)

• Pneumococcal vaccine should be offered as for HIV-negative individuals (recommendation grade B)

• Immunization against hepatitis A and B should be offered to seronegative MSM and PWID (recommendation grade D)

Immunization with live vaccines

• Immunization against measles, mumps, rubella (MMR), yellow fever, varicella, herpes zoster, influenza (nasal vaccine) and typhoid fever (oral vaccine) can be given to PLHIV with suppressive ART and CD4 ≥ 200 (CD4 ≥ 15%) (recommendation grade B)

• Live vaccines should be avoided when CD4 < 200 (despite effective ART) as no data is available for this group of patients (recommendation grade D)

• BCG vaccine should not be given (recommendation grade D)

HPV vaccine

Recommendation

• PLHIV (females and males) aged 11–18 years should be offered HPV vaccine, preferably before sexual debut (recommendation grade A for females, B for males)

Background

Several studies show adequate antibody response after HPV vaccination in PLHIV, but slightly lower levels of seroconversion have been seen in women with CD4 < 200 and/or HIV RNA >10,000 copies/ml [113–115]. There are still no studies regarding duration of vaccine antibody response and effect against HPV infection in PLHIV, but the effect is expected to be equal to that in the general population. Since 2012 HPV vaccine is part of the general immunization programme for girls, which with time will reduce the need for immunizing adults. In mid 2017, the Swedish Public Health Authority proposed that the vaccine should also be offered to boys and the proposal has been sent to the government for decision. Currently, a majority of Swedish children (boys and girls) living with HIV are immunized against HPV. Although it has not been shown to be cost effective to immunize the general population >26 years of age, discussions regarding immunization for PLHIV >26 years are ongoing [116].

Antiretroviral treatment for children and adolescents with HIV

More than 90% of children living with HIV globally were infected vertically by their mother during late pregnancy, during delivery, or through breast-feeding. Currently, about 115 children and adolescents younger than 18 years are known to live with HIV in Sweden. Over the past 10 years, three children born to women with known HIV infection have been infected with HIV. Every year about 60–80 children are born to HIV-infected women in Sweden, giving a transmission rate of <0.5%. These good results have been achieved through a well-developed and widely accepted screening of pregnant women, as well as through effective and freely available prevention of mother-child transmission of HIV [117]. In addition to these children born to known HIV infected women, we are aware of three cases of mother to child transmission in Sweden during the same time period, where the mother’s HIV infection was not known at birth. In one of these cases, the woman tested HIV negative early in pregnancy, but was either infected later in pregnancy or during breast feeding. In the other cases the women were not tested during pregnancy. However, every year a number of HIV infections are diagnosed in children and adolescents who have immigrated to Sweden or were adopted from endemic areas. Two children have died of HIV related causes in Sweden during the last decade.

Before starting treatment

The principles of ART in children do not differ much from adult treatment but do require some special considerations. As the child is dependent on its guardians for good treatment adherence, the whole family situation should be considered prior to treatment initiation. It can be difficult to maintain good adherence in the treatment of an asymptomatic young child if the guardian does not understand the importance of treatment and/or lacks motivation. The importance of adherence and how this must be maintained should be discussed carefully with the child and his/her guardians before initiating treatment.

Perinatal infection occurs during a period when the immune system is under development. The immune system is not capable to limit the viral load, which becomes higher than in adults. This initial very high viral load persists for up to 5 years [118]. When ART is initiated it usually takes longer for young children to reach undetectable HIV RNA levels compared to adults [119]. Absolute CD4 counts typically vary with age in young children [120]. CD4 percentages also vary with age, but not as much as the absolute value [121]. Discrepancy between these parameters is common and age adjusted absolute CD4 counts have been shown to correlate better to immune response than the CD4 percentages in children of all ages [122].

When to start ART in children and adolescents

Children and adolescents living with HIV are recommended ART irrespective of CD4 counts. However, it is important that the child and their family have knowledge about the treatment and how it works. Basic facts about HIV should be taught, aiming to increase understanding of the importance of good adherence and life-long treatment duration. The age and immune status of the child determine the urgency of treatment initiation, and the intensity of information and motivational work. Postponed treatment can be considered in the following cases:

• The patient and/or his/her family are not sufficiently prepared for the treatment and the patient has acceptable CD4 counts (>500 cells/µl)

• The patient has stable CD4 counts >500 cells/µl and non-detectable or very low viral load, including ‘elite controllers’

The reason for postponed treatment is to optimize conditions for good long-term adherence and effective treatment.

It is difficult to predict the risk of developing AIDS and of death among children <1 year of age, but data show good effect of early ART on survival and reduced morbidity in infants [123,124], as well as on cognitive development [125]. Data from paediatric studies support assumptions that early ART initiation leads to improved immunological response, improved growth, decreased inflammation and viral reservoir, and probably better response to immunizations [126–129]. HIV RNA >100,000 copies/ml in older children has been associated with increased risk of mortality [123], as well as with impaired neurocognitive function [130]. Randomized controlled trials in children 5–10 years of age with good immune status do not exist but theoretically even this group should benefit from early ART initiation. Extrapolation of adult data implies treatment of all adolescents, i.e. 11–18 year olds. Treatment of adolescents also reduces risk of transmission to partners when the adolescents become sexually active [19].

The clinical course and symptomatology of HIV infection differs somewhat between children and adults. In paediatric HIV care, the clinical classification developed by the CDC in 1994 and updated in 2014 is used [131].

Initial treatment for children

Resistance testing should always be performed before starting treatment. The choice of medicines for paediatric use has developed greatly and registration of both new and older drugs for use in younger children is ongoing. The formulation, taste and tablet size are more important than in adult treatment. Dosing for children is calculated by weight or body surface area and age. Because children grow rapidly regular and frequent follow up is important in order to be able to adjust the dose. Correct dosage can be obtained by liquid formulations, or with tablets of different strengths. Some drugs are difficult to use in tablet form, as the choice of tablet strengths is limited.

The choice between NNRTI, INSTI and PI is decided upon as for adults. For dosages, see Appendix 1.

Recommended first line treatment for treatment naïve children

0 to <14 d:

zidovudine/lamivudine + nevirapine

zidovudine/lamivudine + raltegravir

14 d to <3 months:

zidovudine + lamivudine + lopinavir/r

zidovudine/lamivudine + raltegravir

3 months to <3 years:

abacavir/lamivudine + lopinavir/r

abacavir/lamivudine + raltegravir

3 to <6 years:

abacavir/lamivudine + atazanavir/r

abacavir/lamivudine + darunavir/r

abacavir/lamivudine + efavirenz

abacavir/lamivudine + dolutegravir

6 to <12 years:

abacavir/lamivudine + atazanavir/r

abacavir/lamivudine + darunavir/r

abacavir/lamivudine or TAF/emtricitabine + efavirenz

abacavir/lamivudine or TAF/emtricitabine +  dolutegravir

≥12 years

abacavir/lamivudine + atazanavir/r

abacavir/lamivudine + darunavir/r

abacavir/lamivudine or TAF/emtricitabine +  dolutegravir

abacavir/lamivudine or TAF/emtricitabine + efavirenz

elvitegravir/cobicistat/emtricitabine/TAF

NRTIs

• For children ≥ 3 months to <6 years old the first-line choice is abacavir + lamivudine. These drugs are available as syrup and scored pills, which increases flexibility and makes them easy to dose in the treatment of growing children. They may be administered once/day from three years of age. HLA-B*5701 testing should be performed before initiating therapy, and abacavir should not be used if the test is positive.

• Tenofovir disoproxil fumarate (TDF) may be used as first-line NRTI from 12 years of age. It is registered from 2 years of age, but because of potential nephrotoxicity and effect on bone mineralization, caution should be taken when using tenofovir in younger children, non-completed puberty and in combination with PI/r.

• Tenofovir alafenamide (TAF) can be used in children ≥ 6 years with a body weight of ≥ 35 kg.

• Zidovudine + lamivudine is an alternative for children of all ages when other NRTIs are not appropriate. However, zidovudine should be avoided when possible because of its adverse effects.

• Emtricitabine is registered for use from 4 months of age. However, with the formulations available in Sweden it can only be used in children and adolescents weighing at least 33 kg.

• Didanosine and stavudine should not be used because of adverse effects.

NNRTIs

• Efavirenz has been shown to be more effective than nevirapine in children >3 years [132].

• Improvements in metabolic parameters have been observed in children switching from LPV/r to efavirenz (EFV) at or after three years [132].

• Plasma drug level measurements are recommended at approximately 3 weeks after efavirenz initiation because of the risk of CNS adverse reactions and very high blood drug levels in carriers of certain genetic CYP2B6 variants [133].

• Nevirapine is an option for children <3 years.

• Etravirine is an alternative medicine registered from six years of age 6 but it lacks suitable formulations for children weighing <30 kg.

• Rilpivirine is registered for treatment of naïve patients from 12 years of age with a viral load of ≤ 100,000 HIV-1 RNA copies/ml. Low resistance threshold.

PI/r

• The first choice for children aged 14 d–3 years is lopinavir/r.

• Lopinavir/r should normally not be used in children younger than 14 d and/or younger than 42 weeks gestational age because of case reports of suspected toxicity in prematurely born children (transient adrenal insufficiency, life-threatening bradyarrhythmia, cardiac effects, lactic acidosis, acute renal failure, central nervous system, and respiratory depression). The toxicity may be due to the drug itself, or to the 15.3% propylene glycol and/or 42.2% ethanol included in the oral solution [134]. If, due to lack of alternatives, the medicine is given to children <14 d of age and/or less than the equivalent of 42 gestational weeks, this should be done during in-patient care under close observation (recommendation grade D).

• From the age of three years darunavir/r and atazanavir/r are first-line choices.

Fusion and entry inhibitors

• Enfuvirtide can be used from 6 years of age

• Maraviroc is not registered for use in children and adolescents <16 years

INSTIs

• Raltegravir is registered for use from 4 weeks of age and is the first-line choice for children 3–11 years old.

• Elvitegravir is registered for use in children and adolescents >12 years old in the combination Genvoya (with emtricitabine, cobicistat and TAF).

• Dolutegravir is a first line choice from age >6 years. Ongoing studies include children as young as four weeks [135].

• Bictegravir is only available in fixed dose combination with TAF/emtricitabine. Not approved for paediatric use but studied in adult dose for children and adolescents aged 12–18 years weighing ≥ 35 kg.

Prophylaxis against Pneumocystis jirovecii

• <1 year → initiate if CD4 < 750 cells/µl

• 1–5 years → initiate if CD4 < 500 cells/µl

• >5 years → initiate if CD4 < 200 cells/µl

When ART is initiated PCP prophylaxis is not always needed, irrespective of CD4 count, if the patient is monitored closely and immunosuppression is not too severe.

Prophylaxis can be stopped after 6 months if CD4 cell levels normalize. An alternative to oral trimethoprim/sulphamethoxazole used in special cases is dapsone or inhalation/intravenous pentamidine. Routine primary prophylaxis against other opportunistic infections is not recommended.

Follow-up

Clinical follow-up including monitoring of HIV RNA every three months is a minimum. CD4 counts do not need to be monitored at all visits in stable patients. Clinical symptoms, adverse reactions, adherence problems and high viral load require more frequent follow-up because immune status may deteriorate rapidly.

Care and treatment of children and adolescents living with HIV should be performed by a team with expertise in HIV care and paediatrics. Sampling should be done at a clinic with an environment adapted to children. Child and family need access to paediatric psychosocial care. Many children living with HIV also need other paediatric medical care, nutritional support, and neuropsychiatric assessments. It is advantageous is these are well integrated in the HIV care. The child/adolescent should also be offered age-adapted education to be able to accept and learn to live with a chronic disease involving complex situations. This includes understanding mode of transmission and of safe sexual debut with a sexually transmitted disease listed under the Communicable Diseases Act. They need to be knowledgeable about their disease, its treatment and how to live with HIV without putting themselves or others at risk. A structured plan for transition from paediatric care to an adult infectious disease clinic should be made in collaboration between these clinics [136]. Access to sexologist expertise is of great value in this phase.

Summary of ART initiation for children and adolescents:

Treatment is recommended to all children and adolescents with HIV.

Delayed treatment start can be considered in the following situations:

• The patient and/or family are not adequately prepared for treatment and the patient has an acceptable immune status (CD4 > 500 cells/μl).

• The patient has stable CD4 counts above 500 cells/μl and undetectable or very low virus levels, including ‘elite controllers’

Management of important adverse effects of antiretroviral therapy

Lipoatrophy

Lipoatrophy, i.e. loss of subcutaneous fat especially in the face and extremities, is a stigmatising adverse effect seen after long time use of stavudine, zidovudine (evidence level 1), and didanosine. Modern ART does not cause lipoatrophy [135].

Metabolic disorders

The most common causes of metabolic disorders in PLHIV are the same as in people without HIV infection, i.e. smoking, poor diet, lack of exercise and heredity. HIV treatment in itself is associated with metabolic disorders, particularly boosted PIs (evidence level 2a). Some of the adverse effects, such as elevated LDL-cholesterol and triglycerides, are usually reversible. Clinical trials have reported improvement in lipid levels after switching to atazanavir, abacavir, tenofovir or NNRTI-based ART [137–139].

In the case of hyperlipidaemia, the overall risk of cardiovascular disease is assessed in accordance with national guidelines. When assessing treatment needs for hyperlipidaemia, risk factors such as smoking habits, diabetes, known cardiovascular disease, heredity, hypertension, etc. should be considered. Increases in cholesterol levels with high LDL are likely to have greater consequence than isolated triglyceride increases. Several algorithms can be used to calculate an individual’s risk of cardiovascular disease, such as the SCORE algorithm [140].

Treatment of metabolic disorders:

• Smoking cessation is always recommended.

• Patients should be given information about appropriate diet and exercise, and referral to a dietician may be considered.

• HIV treatment should be reviewed to minimize the metabolic impact. A decision to change HIV treatment should not compromise the virological control.

If the measures taken do not have the desired effect, lipid-lowering therapy should be considered in accordance with the current guidelines for HIV negative individuals. Statins are the first line choice as follows:

Simvastatin and lovastatin are contraindicated with the entire class of PIs and EVG/c/FTC/TDF and EVG/c/FTC/TAF due to pronounced interaction leading to greatly increased simvastatin levels and a substantial risk of serious muscular adverse effects [141,142]. Patients and other physicians who may be involved in the patients’ other care need to be informed of this. Efavirenz reduces exposure to simvastatin by approximately 60%, which may require higher doses (see Efavirenz SPC). Dolutegravir and raltegravir do not interact with statins.

Other statins should also be dosed with caution and be given initially at low doses together with boosted PI and elvitegravir.

PLHIV who have or who develop diabetes mellitus should be treated as other diabetic patients. HIV treatment should be adjusted as in hyperlipidaemia.

Hepatic effects

In PLHIV with underlying chronic liver disease elevated liver function tests are often seen ​​after initiation of treatment [143]. The liver function test elevation is usually moderate and reversible with a gradual return to original levels upon termination of treatment.

Renal effects

HIV-associated nephropathy is the most common cause of chronic renal failure in PLHIV. This condition is seen almost exclusively in African patients and can occur at any CD4 level. Typically, the condition is due to untreated infection and improvement is often seen after ART initiation.

Tenofovir, as TDF, is associated with a decrease in estimated GFR, acute renal failure, tubular dysfunction, and Fanconi syndrome [144,145]. This is mainly seen in co-treatment with PI/r or cobicistat, which leads to 30% higher tenofovir exposure compared to TDF in combination with NNRTIs, dolutegravir or raltegravir. The nephrotoxic effect of TDF in combination with NNRTI and INSTI in patients with a normal renal function has little or no clinical relevance [146]. This risk of renal dysfunction has not been seen with tenofovir given as TAF [147,148].

Importantly, several ARVs (dolutegravir, cobicistat and rilpivirine) inhibit tubular secretion of creatinine, leading to immediate increase in plasma creatinine levels and concurrently an estimated reduced glomerular filtration rate (GFR). However, this change in creatinine levels does not progress after the initial increase. It does not affect GFR and is not considered clinically relevant [149].

Hypersensitivity reactions

Hypersensitivity and/or rash may occur during treatment with any antiretroviral agents, but the most serious cases have been reported for abacavir (evidence level 4).

About 5% of patients develop hypersensitivity reactions (HSR) on abacavir treatment, usually in the form of fever, rash, and general malaise (for details, see Kivexa SPC). If treatment with abacavir is continued or resumed after being interrupted after HSR there is a risk of severe HSR and fatalities have been reported (evidence level 1c). The presence of the HLA class 1 allele HLAB*5701 is highly associated with the risk of severe HSR [150,151]. HLAB*5701 prevalence varies between different populations, from 5 to 10% among white Europeans to less than 1% of PLHIV of African origin [152]. Genotyping for HLAB*5701 should be performed prior to initiation of abacavir. In patients positive for HLAB*5701 abacavir is contraindicated [153].

Rash and other dermatological reactions are relatively common even with efavirenz, etravirine and dolutegravir, although usually of mild or moderately severe degree (SPC Stocrin, Intelence and Tivicay).

Darunavir should be used with care in patients who have previously had allergic reactions to sulpha as darunavir contains a sulphonamide part and is therefore prone to cross-reactivity in severe sulpha allergy.

Drug–drug interactions

The large risk of drug–drug interactions, mainly in treatment with PIs and NNRTIs treatment, requires a thorough assessment of all co-treatment when ART is initiated or modified; this also pertains to situations when concentration-dependent side effects of a medicine are suspected. For an overview of potential interactions please see relevant website, e.g. http://www.hiv-druginteractions.org/. A clinical pharmacologist can also be consulted.

NRTIs

Most NRTIs are mainly excreted renally. They are not metabolized or affected by CYP450 enzymes and, therefore, pose a low risk of pharmacokinetic drug–drug interactions.

NNRTIs

NNRTIs are CYP450 substrates. Most NNRTIs also induce several CYP450 enzymes, which may result in decreased concentrations of co-administered medications that are eliminated through metabolism. A clinically important example is methadone, the levels of which can also be decreased in co-treatment with PI/r, though usually to a lesser degree. Other examples include some statins, which may have to be given in higher doses (simvastatin, lovastatin), and platelet inhibitors whose effect may be reduced due to lower exposure (clopidogrel, ticagreolor). An exception is the antiplatelet agent clopidogrel with etravirine. Etravirine inhibits CYP2C19 (the main metabolizing enzyme of clopidogrel) and the combination therefore instead causes increased exposure and risk of bleeding.

Co-treatment with NNRTI and PI/r may be challenging due to enzyme induction (see respective SPCs). Other enzyme-inducing medicines such as carbamazepine and rifampicin cause decreased concentrations of NNRTIs and increased doses may be considered.

PIs

All PIs, especially ritonavir, are potent inhibitors of CYP3A, which causes great numbers of potential drug interactions. Ritonavir (and darunavir and lopinavir) also induce the activity of some CYP enzymes, which complicate the interactions further. This means that exposure to pure CYP3A substrates increases when given with PI/r, whereas exposure to medicines that are metabolized through several CYP-enzymes usually decreases. An example of this is methadone (25% decrease in exposure). Cobicistat is a recently approved specific inhibitor of CYP3A without antiretroviral activity, but is used to increase exposure to elvitegravir, atazanavir, and darunavir. In contrast to ritonavir cobicistat does not induce drug metabolizing enzymes (including CYP enzymes). When prescribing to patients treated with PI/r, the risk of drug-drug interaction should always be kept in mind. Some medicines are contraindicated, whereas others require dose adjustments. Examples of clinically important interactions include:

• Statins: Simvastatin and lovastatin are contraindicated with concomitant PI/r or elvitegravir/c treatment. Atorvastatin and rosuvastatin also interact with boosted PI and elvitegravir/c, but the combinations are not contraindicated. The lowest possible dose should be given and thereafter be increased while monitoring the patient [154,155]. When initiating statin treatment in a patient treated with PI or elvitegravir the respective SPCs should be consulted.

• Antihypertensives: Risk of increased exposure to calcium channel inhibitors, which should, therefore, be used with caution. Calcium channel inhibitors with effects on the cardiac conduction system should be avoided when alternative treatment exists. No clinically relevant interactions are expected for beta-blockers, diuretics and ACE-inhibitors.

• Antiplatelet agents: Clopidogrel undergoes bioactivation through CYP metabolism (CYP2C19). The concentration of active metabolites and thereby the antiplatelet activity may therefore be reduced in co-treatment with boosted PI and elvitegravir. However, atazanavir given without booster probably does not significantly affect these medicines. In contrast, the concentration of ticagrelor (metabolized mainly through CYP3A) increases greatly, leading to increased risk of bleeding. The combination of boosted PI or elvitegravir with ticagrelor is therefore contraindicated. In co-treatment with inducers (e.g. efavirenz) the effect is the opposite (reduced exposure to ticagrelor). The exposure to prasugrel, although bioactivated by CYP enzymes, is not significantly affected in co-treatment with a potent CYP3A-inhibitor (ketoconazole) or strong inducer (ritonavir), and should therefore be possible to give with all recommended ART. The following ARVs can be administered without dose adjustments:

  • ○ With prasugrel: no clinically significant interactions expected with recommended ART

  • ○ With clopidogrel: all NRTIs, dolutegravir, raltegravir, atazanavir without ritonavir, rilpivirine

  • ○ With ticagrelor: all NRTIs, dolutegravir, raltegravir, rilpivirine

• Medicines against erectile dysfunction: The concentration of sildenafil, tadalafil and vardenafil increases greatly when given with boosted PIs and elvitegravir/c and should therefore be given at the lowest possible doses at intervals according to the respective SPCs.

• Benzodiazepines: Increased exposure to, e.g. diazepam, alprazolam, flunitrazepam, and others during co-treatment with ARVs. Oxazepam is an exception, and is recommended at a dose titrated according to clinical response.

• Inhalational steroids (including nasal administration): The concomitant use of highly potent inhalation steroids such as fluticasone and PI/r has been shown to cause Cushing syndrome. Beclomethasone is an alternative not expected to interact with PI/r or elvitegravir/c.

• Immunosuppression: Cyclosporin, tacrolimus, sirolimus and everolimus are all metabolized by CYP3A4 and the blood concentration may therefore increase markedly with concomitant treatment with PI/r and elvitegravir/c. The latter drug’s inhibition of the transport protein P-glycoprotein contributes to further concentration increase of immunosuppressants. Immunosuppression must be given at a low dose with careful monitoring of drug concentration.

INSTIs

Dolutegravir does not affect CYP450 enzymes and treatment is therefore not expected to affect the pharmacokinetics of other drugs to the same extent as PI and NNRTI. An important exception is the commonly used medicine metformin, which increases in concentration in co-treatment and must therefore be given at a low dose. Dolutegravir is eliminated mainly through UGT1A1 but is also metabolized to a certain extent through CYP 3A4 and other medicines may therefore affect dolutegravir exposure. Dolutegravir exposure decreases in co-treatment with inducers such as efavirenz, carbamazepine, and rifampicin. In such co-treatment in patients without INSTI resistance dolutegravir should be given twice daily. The co-treatment should not be given in patients with suspected or confirmed INSTI resistance. Raltegravir and elvitegravir interact similarly to dolutegravir. Note that elvitegravir is given in fixed combinations containing cobicistat, which inhibits CYP3A and thereby interacts with several other medicines (see PI above).

Interaction with antacids and ion complex forming agents

Patients who often need antacids should preferably not be treated with rilpivirine (co-treatment with proton pump inhibitors contraindicated). Atazanavir absorption is also markedly decreased, and other medicines should be chosen (unboosted atazanavir is contraindicated). Follow recommendations in respective SPCs.

Medicines containing divalent cations (Ca2+, Fe2+, Mg2+) should not be administered together with INSTI (this leads to chelate complex formation in the gastrointestinal tract). However, if the medicines are taken at least 4 h apart absorption is not affected. For detailed information, see respective summary of product characteristics (SPC) (note, however, that these do not consider additive effects). Typical examples of products containing divalent cations are calcium substitution, multivitamins, iron replacement medicines and antacids.

Interactions with oral contraceptives

Ritonavir induces the metabolism of norethisterone, levonogestrel, and ethinylestradiol [156]. This probably reduces concentrations of the contraceptives, and a reduced contraceptive effect cannot be ruled out. The exception is atazanavir/r where evidence shows that co-treatment with ethinylestradiol (35 µg) and norgestimat (Cilest^®) gives good anti-conceptive effect (SPC Reyataz). Oral contraceptives are not recommended in co-treatment with efavirenz or nevirapine because of decreased exposure to the contraceptive medicines. Other forms of contraception should therefore be used when treating with these NNRTIs.

Interactions with antiepileptics

Carbamazepine, phenytoin and phenobarbital are enzyme inducers and can lower concentrations of all PIs, NNRTIs, INSTI and maraviroc. Plasma concentration of the antiepileptic can also be affected in either direction. Valproic acid and lamotrigine are glucuronidated and their concentrations decrease in co-treatment with ritonavir. Gabapentin, vigabatrin and levetiracetam are excreted renally and have a low potential for interactions with ARVs. Neurologists traditionally use therapeutic drug monitoring for dose titration and this can be a valuable tool even for handling potential ART interactions.

Interactions with herbal remedies

Several studies have demonstrated that St. John’s worth (Hypericum perforatum) is a very potent inducer of CYP enzymes and the transport protein P-glycoprotein. The use of St. John’s worth is therefore contraindicated in patients on ART. In general, knowledge about interactions between medicines and herbal remedies is very limited and the content of these remedies is not controlled, and general caution is recommended regarding their use in combination with ART.

Food–drug interactions

Several ARVs have clinically significant drug-food interactions. Tenofovir, rilpivirine, elvitegravir and all PIs (except lopinavir/r pills) should be taken with food as bioavailability is lower when fasting. In patients without drug resistance tenofovir does not have to be taken with food. Therefore, the combination tablet Atripla^® is recommended to be taken when fasting as the risk of CNS side effects with efavirenz is lower in this state (SPC Atripla, Stocrin).

Therapeutic drug monitoring of ARVs

Routine measurement of plasma concentrations of antiretroviral medicines is not recommended, but may be considered in the following circumstances:

• Concomitant treatment with potent inducers of drug metabolism (such as rifampicin, carbamazepine, phenytoin), or other substances that decrease ARV plasma concentration

• Treatment of pregnant women or children, in cases of clinically significant drug resistance

• Concentration-dependent adverse effects of efavirenz and dolutegravir (CNS adverse effects after more than a month of treatment)

• Severe hepatic or renal impairment

• Treatment failure

• Suspected poor adherence to treatment

Monitoring should generally be performed when the ARV has reached steady state, which for most medicines means after at least 10-14 days of treatment. Trough values are recommended where possible as these correlate best to effect and show the least variability.

Disclosure statement

The authors declare that they have no conflicts of interest related to the submitted paper.

Appendix 1. Paediatric and adolescent dose recommendations for antiretrovirals

Table

Name	Formulation	Neonate	Paediatric/adolescent	Comment
Nucleoside reverse transcriptase inhibitors (NRTI)
Abacavir (ABC) Ziagen Generics available	Syrup 20 mg/ml, Film-coated tablet 300 mg (scored tablet)	Not registered < 3 months (8 mg/kg × 2 ongoing study)	Syrup: 8 mg/kg × 2 (max 300 mg × 2) Tablet: 14-21 kg, 150 mg × 2 22 kg to < 30 kg, 150 mg in the morning and 300 mg in the evening 30 kg, 300 mg × 2, alt. 600 mg × 1 Adult dose given ≥ 12 years	Dosed once daily for children ≥ 3 years. HLA B*5701 must be tested before use. Can be given with or without food.
Emtricitabine (FTC) Emtriva	Capsule 200 mg	Not registered < 3 months	≥ 33 kg, capsule 200 mg × 1 Adult dose given ≥ 12 years	Can be given with or without food.
Lamivudine (3TC) Epivir Zeffix	Syrup 10 mg/ml, Film-coated table 150 mg (scored) and 300 mg, Film-coated tablet 100 mg (Zeffix)	< 30 days, 2 mg/kg × 2	Syrup: 4 mg/kg × 2 Tablet: 14 kg for < 19 kg, 75 mg × 2 19 kg for < 25 kg, 100 mg × 2 25 kg for < 30 kg, 75 mg in the morning and 150 mg in the evening 30 kg, 150 mg × 2, alt. 300 mg × 1 Adult dose given ≥ 12 years	Dosed once daily for children ≥ 3 years Can be given with or without food.
Tenofovir disoproxil fumarate (TDF) Viread Generics available	Viread, Oral powder 33 mg/g Film-coated tablet 123 mg, 163 mg, 204 mg and 245 mg	Not registered < 2 years	Oral powder: 6,5 mg/kg × 1 (max 245 mg × 1) Tablet (6 to < 12 years): 17 kg to < 22 kg, 123 mg × 1 22 kg to < 28 kg, 163 mg × 1 28 kg to < 35 kg, 204 mg × 1 ≥ 35 kg, 245 mg × 1 Adult dose given ≥ 12 years	Should be taken with food. High fat content increases absorption. Use cautiously in younger children, pre-puberty and in combination with PI/r
Zidovudine (ZDV) Retrovir	Syrup 10 mg/ml Capsule 100 mg and 250 mg, Film-coated tablet 300 mg (scored) Solution for infusion 10 mg/ml (dilute to 2 mg/ml)	Premature: < week 30: 2 mg/kg if po and 1,5 mg/kg if iv bid, after 4 w increase dose to 3 mg resp. 2,3 mg bid w 30 to < w 35: 2 mg/kg if po and 1,5 mg/kg if iv bid, after 2 w increase dose to 3 mg resp. 2,3 mg bid Full term (≥ v 35) < 3 months, 4 mg/kg × 2 (3 mg/kg × 2 if iv)	4 kg to < 9 kg, 12 mg/kg × 2 9 kg to < 30 kg, 9 mg/kg × 2 ≥ 30 kg, 300 mg × 2 Adult dose given ≥ 12 years	Can be taken with food.
Fixed combinations
Atripla	Film-coated tablet (600/200/245 mg EFV/ FTC/TDF)		≥ 12 years and ≥ 40 kg, 1 × 1
Bictarvy	Film-coated tablet (50/200/25 mg BIC/FTC/TAF)		> 18 years, 1 × 1
Combivir	Film-coated tablet (300/150 mg ZDV/3TC)		≥ 12 years or ≥ 30 kg, 1 × 2
Descovy	Film-coated tablet (200/25 mg, 200/10 mg FTC/TAF)		≥ 6 years or ≥ 35 kg, 1 × 1
Eviplera	Film-coated tablet (200/25/245 mg FTC/RPV/TDF)		≥ 18 years, 1 × 1	Use cautiously if HIV RNA > 100.000 copies/ml because of risk of virological failure
Genvoya	150 mg/150 mg/200 mg/10 mg (EVG/ COBI/ FTC/TAF)		≥ 12 years or ≥ 35 kg, 1 × 1
Kivexa Generics available	Film-coated tablet (600/300 mg ABC/3TC)		≥ 12 years or ≥ 30 kg, 1 × 1	The Arrow study indicates that Kivexa can be given to children ≥ 25 kg
Odesfey	Film-coated tablet (200/25/25 mg FTC/TAF/RPV)		≥ 12 years or ≥ 35 kg, 1 × 1	Use cautiously if HIV RNA > 100.000 copies/ml because of risk of virological failure
Stribild	Film-coated tablet (150/150/200/245 mg EVG/COBI/FTC/TDF)		≥ 18 years, 1 × 1
Symtuza	Film-coated tablet (10/800/200/150 mg TAF/DRV/FTC/COBI)		≥ 12 years and ≥ 40 kg, 1 × 1	Given with food
Trizivir	Film-coated tablet (300/150/300 mg ABC/ 3TC/ZDV)		≥ 16 years, 1 × 2	Not first line treatment for children and adolescents
Triumeq	Film-coated tablet 50 mg/ 600 mg/ 300 mg (DLG/ABC/3TC)		≥ 12 years and ≥ 40 kg, 1 × 1
Truvada Generic available	Film-coated tablet (200/245 mg FTC/TDF)		≥ 12 years or ≥ 35 kg, 1 × 1
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Efavirenz (EFV) Stocrin Generics available	Tablet 50 mg, 200 mg and 600 mg Syrup 30 mg/ml	Not registered	Syrup to children 3 - <5 years: 13 - < 15 kg, 360 mg × 1 15 - < 20 kg, 390 mg × 1 20 - < 25 kg, 450 mg × 1 25 - < 33 kg, 510 mg × 1 Syrup to children ≥ 5 years 13 - < 15 kg, 270 mg × 1 15 - < 20 kg, 300 mg × 1 20 - < 25 kg, 360 mg × 1 25 - < 33 kg, 450 mg × 1 33 - < 40 kg, 510 mg × 1 ≥ 40 kg, 720 mg × 1 Tablets irrespective of age 10 - < 15 kg, 200 mg × 1 15 - < 20 kg, 250 mg × 1 20 - < 25 kg, 300 mg × 1 25 - < 33 kg, 350 mg × 1 33 - < 40 kg, 400 mg × 1 ≥ 40 kg, 600 mg × 1	S-concentration 14-21 days after treatment initiation. Recommended concentration 3.3 to 12.7 μmol/L 12 to 20 hours after dose intake. Should be taken without food at bedtime. Foods high in fat increase bioavailability.
Nevirapine (NVP) Viramune Generics available	Tablet 200 mg and 400 mg Slow-release tablet 50 mg and 100 mg Syrup 10 mg/ml	5 mg/kg or 120 mg/m^2 × 1 for 14 days, followed by 5 mg/kg or 120 mg/m^2 × 2 for 14 days, followed by 200 mg/m^2 × 2 (until 2 months age)	120-200 mg mg/m^2 × 2. Start with 120 mg/m^2 (max dose 200 mg) × 1 i 14 days. If there are no skin eruptions or other adverse effects, increase to full dose = < 8 years 7 mg/kg or 200 mg/m^2 × 2 (max dose, 200 mg × 2) ≥ 8 years 4 mg/kg or 120 mg/m^2 × 2 (max dose, 200 mg × 2)	NVP is initiated in low doses and increased gradually for induction of CYP450 metabolizing enzymes, resulting in increased clearance. Skin eruptions rates are decreased by the gradual increase. Can be taken with or without food.
Rilpivirine (RPV) Edurant	Film-coated tablet 25 mg		≥ 12 years with viral load ≤ 100.000 HIV-1-RNA-copies/ml	Should be taken with food. Part of fixed combination Eviplera
Protease Inhibitors (PI)
Atazanavir (ATV) Reyataz	Capsule 150 mg, 200 and 300 mg	Not registered. Not given to children < 3 months because of risk of hyperbilirubinaemia (kernicterus).	< 6 years: Not registered. Dose 6-18 years: Boosted with Ritonavir (ATV/RTV). 15 kg to < 20 kg, 150/100 mg × 1 ≥ 20 kg to < 40 kg, 200/100 mg × 1 ≥ 40 kg, 300/100 mg × 1	Should be taken with food. ATV should possibly be increased to 300 mg if ≥35 kg to avoid under dosing, especially during co-treatment with tenofovir
Darunavir (DRV) Prezista	Oral suspension 100 mg/ml Tablet: 75 mg, 150 mg, 400 mg, 600 mg and 800 mg	Not registered.	< 3 years: Not registered. Dose 3-17 years Boosted med Ritonavir (DRV/RTV) Treatment naive: 15 to < 30 kg, 400/100 mg × 1 30 to < 40 kg, 475/100 mg × 1 > 40 kg, 800/100 mg × 1 Previously treated: Syrup: 15 to < 30 kg, 380/50 mg × 2 30 to < 40 kg, 460/60 mg × 2 > 40 kg, 600/100 mg × 2 Tablet/Syrup: ≥20 to <30 kg, 375/50 mg × 2 ≥30 to <40 kg, 450/60 mg × 2 ≥40 kg, 600/100 mg × 2 Adolescent (≥ 12 years and 40 kg): 800 mg/100 mg × 1 ≥ 18 years, previously treated 600/100 mg × 2 With Maraviroc: 600/100 mg × 2 + 150 mg MVC × 2	Should be taken with food.
Lopinavir/Ritonavir (LPV/RTV) Kaletra	Tablet 200 mg LPV/50 mg RTV, Tablet 100 mg LPV/25 mg RTV, Syrup (NB! contains 42,4 % ethanol) 80 mg LPV/20 mg RTV/ml	Registered from 2 years Not together with NVP or EFV: Should not be used first weeks of live because of lacking documentation and suspected toxicity in premature children (FDA U.S. Food and Drug Administration. FDA Drug Safety Communication). Dose 14 days – 6 months age: LPV/RTV 16 /4 mg /kg × 2	Registered from 2 years Not together with NVP or EFV: 6 months – 18 years: LPV/RTV Syrup: 7 - < 15 kg, 12/3 mg /kg × 2 15 to 40 kg, 10/2,5 mg /kg × 2 > 40kg: 400/100 mg × 2 Tablet 15 - < 25 kg, 200/50 mg × 2 ≥ 25 - < 35 kg, 300/75 mg × 2 ≥ 35 kg, 400/100 mg × 2 In combination with NVP or EFV (should normally be avoided): 6 months – 18 years: 7 - < 15 kg: 13/3,25 mg /kg × 2 15 - 45 kg: 11/2,75 mg /kg × 2 600 mg LPV/150 mg RTV × 2 Tablet 15 - < 20 kg, 200/50 mg × 2 ≥ 20 - < 30 kg, 300/75 mg × 2 ≥ 30 kg - < 45 kg, 400/100 mg × 2 ≥ 45 kg, 600/150 mg × 2	Syrup should be taken with food. Tablets can be taken with or without food. If used below one year of age plasma concentration should be monitored
Ritonavir (RTV) Norvir	Film-coated tablet 100 mg, syrup 80 mg/ml			Only used as booster with other PI
Fusion inhibitors (FI)
Enfuvirtide (T-20) Fuzeon	Injection 90 mg/ml	Not registered	Not registered < 6 years. Dose 6–16 years: 2 mg/kg (max dos, 90 mg) × 2 s.c. >16 years = 90 mg × 2 s.c.
Integrase Inhibitors (INI)
Dolutegravir (DLG) Tivicay	Tablet 50 mg	Not registered	Dose ≥ 6 år: 15 kg to < 20 kg, 20 mg × 1 20 kg to < 30 kg, 25 mg × 1 30 kg to < 40 kg, 35 mg × 1 ≥ 40 kg, 1 × 1
Elvitegravir (EVG)				Part of fixed combination Stribild
Raltegravir (RAL) Isentress	Tablet 400 mg Chewable tablet 25 mg and 100 mg (scored) Granulate for syrup 100 mg	Registered from 4 weeks of age	Granulate for syrup 10 mg/ml: Birth to one week of age: 2 kg to <3 kg, 0,4 ml × 1 3 kg to < 4 kg, 0,5 ml × 1 4 kg to < 5 kg, 0,7 ml × 1 1–4 weeks: 2 kg to < 3 kg, 0,8 ml × 2 3 kg to < 4 kg, 1 ml × 2 4 kg to < 5 kg, 1,5 mL × 2 ≥ 4 weeks: 3 kg to < 4 kg, 2,5 ml × 2 4 kg to < 6 kg, 3 ml × 2 6 kg to < 8 kg, 4 ml × 2 8 kg to < 11 kg, 6 ml × 2 Chewable tablet: 11 kg to < 14 kg, 75 mg × 2 14 kg to < 20 kg, 100 mg × 2 20 kg to < 28 kg, 150 mg × 2 28 kg to < 40 kg, 200 mg × 2 > 40 kg, 300 mg × 2 Tablet 400 mg 400 mg × 2 can be given to children weighing ≥ 25 kg	Can be taken with or without food
Boosters
Cobicistat (COBI) Tybos	Film-coated tablet 150 mg		No data < 18 years