Category Archives: 6.6. What to Start With?

6.6. What to Start With?

– Christian Hoffmann –

Once the decision has been made to start, the next question is, what to start with? More than two dozen drugs are now available, and the number of theoretically possible combinations seems to be almost infinite. In most guidelines, more than ten different combinations are recommended as “preferred”, while numerous more are listed as “alternatives”.

It would be brilliant if every treatment-naïve patient participated in a clinical study. That would be the best way to continue improving the quality of antiretroviral therapy. However, in practice it is not always possible to sign everyone up for a clinical trial. For information regarding the treatment of naive patients, the following summarizes the available data.

Recommended Initial Regimens

Combinations that we currently recommend for first-line therapy (as of March 2011) are shown in Table 6.1. In the list, there is no order of preference. Moreover, many other combinations are possible. These other combinations may be acceptable in individual cases or in investigational studies, but general recommendations for their use cannot be given. Problematic drugs or combinations that are not advisable for use are listed at the end of this chapter.

Table 6.1. ART combinations suitable for initial therapy (in no order of preference).

NRTIs

  3rd agent

TDF + FTC

Atazanavir/r (PI)

*ABC + 3TC

plus either

Darunavir/r (PI)
Fosamprenavir/r (PI)
Lopinavir/r (PI)

Alternatives

Saquinavir/r (PI)

AZT + 3TC

Efavirenz** (NNRTI)

TDF + 3TC

Nevirapine*** (NNRTI)Raltegravir**** (INI)
*      Only when HLA typing is possible, caution when risk for cardiovascular events is high.
**     Caution in women of childbearing age (teratogenicity).
***    Beware of hepatotoxicity when CD4 T cells are high (women >250, men >400/µl).
****  Convincing data, but lack of long term experience.

Practical approach to the first regimen – important rules

All current initial regimens consist of two nucleoside analogs combined with either a boosted PI or an NNRTI. No single combination has clearly been shown to be superior to any other. There is no one gold standard. When choosing primary therapy, many factors are involved besides the antiviral potency and tolerability. Individual factors, such as compliance, concurrent illnesses and concomitant medications, as well as the needs of the individual should be included in the decision. One should be aware that primary (first-line) therapy is of great significance and needs to be well prepared for. It is at this time that the chance of viral suppression followed by long-term maintenance of suppression is greatest.

Practical tips for first-line therapy:

  • The first regimen offers the best chance of suppression followed by maintenance. The viral load should decrease to below detection levels within 3-6 months.
  • Do not rush – the patient must be ready for ART. If in doubt, wait and continue to monitor levels.
  • If possible, do not prescribe medication in the first consult with a new patient who brings their results. Do you know the patient well enough? Are they really motivated? Will they come back?
  • For every patient, prescribe the ART they are able to take. Do not insist on theoretically superior combinations.
  • The pros and cons (side effects) of different combinations should be discussed – have enough time for this.
  • The initial regimen should be taken no more then twice daily. Once-daily treatment should be considered if it is important for the patient.
  • The toxicity profiles should not overlap whenever possible – never use several allergenic drugs simultaneously.
  • Ask about other medication (and drug use) – are relevant interactions to be expected?
  • Concomitant illnesses should also be checked – what about the liver (hepatitis), kidneys?
  • All drugs are started on the same day – no “lead-in” mono- or dual therapy.
  • Be sure to check whether the patient would be eligible for a clinical study. All patients, especially if treatment-naïve, should be encouraged to participate in clinical trials, which may help the patient reach a better understanding of the importance of treatment and good adherence. Take your time.

What should be clarified first

Dosing issues & adherence

Can the patient really take drugs several times a day? Do they understand that treatment will probably be lifelong? Is this realistic with regard to the individual, professional and/or social situation? If in doubt, a simpler regimen is preferable to one that is presumed more effective. For example, it is often not realistic to expect patients with adherence problems to take tablets twice a day according to a strict protocol. However, they also need treatment. There have been successful attempts at once-daily regimens for drug users (Staszewski 2000), who might also be suitable for DOT (Directly Observed Therapy) or DAART (Directly Administered ART) together with the substitution program. However, randomized studies have not shown better virological response in the case of DOT (Nachega 2010, Berg 2011). With DAART, response to therapy may probably be improved (Maru 2009). However, the virologic benefit of this strategy wanes following transition to self-administered therapy (Gross 2009, Smith-Rohrberg 2009).

In patients with obvious adherence problems, it should be considered that NNRTI-based regimens that are easy-to-take have a low resistance barrier. Studies such as FIRST have demonstrated that especially in patients with low adherence, the risk for resistance is increased in NNRTI regimens compared to PI regimens (Gardner 2008). Thus, in some cases, a boosted once-daily PI regimen may be preferable. When treatment is not taken 100% on time, the resistance risk may be relatively lower than with PIs than with NNRTIs.

For many patients the numbers of pills or requirements for food intake are important. The range of licensed and recommended initial regimens varies from 2 to 7 pills per day (caution: in many countries, the combination pill Atripla® with one pill QD has not been licensed as first-line).

Some patients find it unacceptable to have to take pills at certain times during the day with fatty foods. Patients today are more demanding than before – justifiably so. There are now alternatives. Even the size or consistency of tablets can be a problem. Such issues must be discussed before initiating therapy as ART needs to become one more part of normal daily life.

Concurrent illnesses

Before starting treatment, possible concurrent illnesses should be identified (anamnesis, examination). This is fundamental in helping make the right choice (Table 6.2).

Table 6.2. Concurrent illnesses requiring caution with specific drugs (not only in first-line therapy). There are no absolute contraindications.
Illness Caution with
Active hepatitis B Nevirapine, boosted PIs (beneficial: Tenofovir+ FTC)
Active hepatitis C Nevirapine, boosted PIs
Active agent use, substitution NNRTIs, ritonavir (possibly beneficial: raltegravir)
Anemia AZT, possibly also 3TC
Arterial hypertension Indinavir
Chronic diarrhea, intestinal diseases Nelfinavir, lopinavir, fosamprenavir, other PIs
Diabetes mellitus PIs
Kidney disease Indinavir, tenofovir, possibly atazanavir
Myocardial infarction Abacavir, ddI, PIs (potentially beneficial: nevirapine)
Pancreatitis ddI
Polyneuropathy d4T, ddI
Psychoses, other CNS illnesses Efavirenz

For example, a patient with diarrhea should not be given fosamprenavir or lopinavir. Use tenofovir or indinavir with caution in patients with renal disease. Atazanavir may also be associated with renal diseases (Mocroft 2010). ddI and d4T are contraindicated in patients with a history of pancreatitis or polyneuropathy and are no longer recommended in first-line therapy. Non-insulin-dependent diabetes can become insulin-dependent with PI treatment. There are some cohort studies that report an association between recent use of abacavir and an increased risk of myocardial infarction (Sabin 2008, Lundgren 2009). Although these observations have not been without debate (Brothers 2009), some experts recommend alternatives when cardiovascular risk is increased (Behrens 2010). However, according to a more recent meta-analysis by the FDA, it has become questionable whether there really is a correlation between abacavir and MI-risk (Ding 2011).

Liver disease and chronic hepatitis must also be taken into account, because the risk of developing severe hepatotoxicity on nevirapine or ritonavir is highest (Sulkowski 2000). Caution is also required with boosted PIs. However, one study conducted in over 1000 patients found no difference between lopinavir/r and an unboosted PI such as nelfinavir in patients coinfected with hepatitis C (Sulkowski 2004). In coinfections with HBV, 3TC or better tenofovir+FTC should be utilized (Avihingsanon 2010). Long term monitoring of HBV over a span of five years or longer is possible with tenofovir (de Vries-Sluijs 2010). However, in HBV-coinfected patients starting ART, two HBV drugs should be integrated in order to reduce the risk of HBV resistance. Avoid Combivir® or Kivexa® in cases of hepatitis B coinfection when no other HBV agent is on board – 3TC alone for HBV is not enough.

Interactions with medications and drugs

Interactions are important in when choosing regimens. Whereas interactions between antiretroviral drugs are well known, those with other medications are often less well characterized (see section on interactions). The urgent need for more research was demonstrated in a study investigating the interactions between ART and lipid lowering agents. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3059% after concurrent dosing with ritonavir or saquinavir (Fichtenbaum 2002). Several cases of fatal rhabdomyolysis on simvastatin, atorvastatin and PIs, such as atazanavir, lopinavir and nelfinavir have been described (Hare 2002, Mah 2004, Schmidt 2007). There is even a case report on pravastatin, a currently favored statin (Mikhail 2009), so boosted PIs should be utilized with caution.

Many other drugs should be avoided in combination with particular antiretroviral drugs, as incalculable interactions may occur. These include certain contraceptives. Even drugs that seem unproblematic at first glance can have unfavorable effects. For example, the plasma levels of saquinavir can be reduced by half with administration of garlic capsules (Piscitelli 2002). Even a seemingly harmless agent, such as vitamin C can influence plasma levels. A small study in healthy volunteers showed that vitamin C can significantly lower (14%) unboosted indinavir levels (Slain 2005). Coumarin derivative anticoagulants, such as warfarin can also be a problem; ritonavir can significantly lower plasma levels (Llibre 2002). Further typical problem drugs include migraine remedies, prokinetic drugs and sedatives/hypnotics. One fatal case was described with ergotamine and ritonavir (Pardo 2003). The simultaneous administration of ART and PDE-5 inhibitors (sildenafil, vardenafil, tadalafil) can also be problematic (see section on Sexual Dysfunction).

Drugs or alcohol can interact with ART (Neuman 2006, Mass 2006). For those in substitution programs, the methadone requirement may be significantly increased by certain antiretroviral drugs, such as nevirapine and efavirenz (Clarke 2001). To a lesser extent, this is also true for ritonavir and nelfinavir. There is inconsistent data on lopinavir but it may also require dose adjustments. Raltegravir, again, seems to have no effects (Anderson 2010).

Other interactions have even more dangerous consequences. Several deaths have been reported after simultaneous dosing with ritonavir and amphetamines or MDMA/ecstasy, the popular narcotic gamma hydroxybutyric acid (GHB) or “liquid ecstasy” (Henry 1998, Harrington 1999, Hales 2000). Ritonavir in particular inhibits the metabolism of amphetamines (speed or MDMA/ecstasy), ketamines or LSD (Antoniou 2002). Clinicians and patients are well advised to have an open conversation about drug use before starting therapy. Marijuana and THC appear to have a low potential for interactions (Kosel 2002). Amphetamines seem to be particularly dangerous and neurotoxic in HIV patients (Chana 2006).

Not every agent can be discussed here. Many are described in the respective drug chapters. It is always recommended to check the package insert. Initiation of ART provides a good opportunity to re-evaluate existing prescribed medications.

Additive toxicities

Several potential additive toxicities should be considered in the choice of therapy. If other myelotoxic drugs (i.e., valgancyclovir, cotrimoxazole) are necessary, caution is required with AZT. When treating hepatitis C with interferon and ribavirin, ddI must be avoided. Ribavirin should not be combined with AZT or d4T. d4T should generally be avoided due to its potentially high toxicity. Tenofovir, indinavir, possibly also atazanavir should also be avoided with potentially nephrotoxic drugs. Lastly, it is not advisable during primary therapy to start with potential allergy-inducing agents if anti-infectious prophylaxis with cotrimoxazole or other sulphonamides is necessary. Included here are nevirapine, efavirenz and abacavir, but also fosamprenavir and darunavir. In order not to upset the prophylaxis, it is better to avoid these ARVs. Otherwise, it can be difficult to clearly identify the causative agent for a drug-induced exanthema.

What drug classes should be used?

All combinations currently used as initial regimens consist of two NRTIs plus either a PI, an NNRTI or the integrase inhibitor raltegravir.  A third NRTI (triple nuke) is only used in exceptional cases and is only briefly mentioned here. All other combinations are currently (April 2011) not justified for use outside the framework of clinical studies. Advantages and problems of these three strategies are outlined in Table 6.3.

Table 6.3. Combining drug classes: Advantages (é) and disadvantages (ê).
2 Nukes + PI 2 Nukes + NNRTI 2 NRTIs + INI
é a lot of data, including cli-nical endpoints and severely immunocompromised pts. é equivalent, perhaps even better suppression of viral load than with PIs é very good efficacy, excellent tolerability
é long-term data available é low pill burden, once-daily may be possible é few interactions
é high genetic resistance barrier é leaves PI options é maintains options
ê high pill burden (for the older PIs), some once-daily regimens not licensed ê clinical effect not proven (only surrogate marker studies) ê no long-term data
ê frequent drug interactions ê less data in severely im-munocompromised patients ê once-daily with raltegravir not possible, high costs
ê some PIs with cross-resistance, leaving limited options ê rapidly occurring complete cross-resistance, low resistance barrier ê No clinical endpoints, no long-term data
ê long-term toxicity, lipody-strophy, dyslipidemia with most PIs ê strict monitoring required initially (esp. nevirapine), allergies frequent ê relatively low resistance barrier

Studies comparing these strategies are listed in Table 6.4. The validity of previous milestone trials such as Atlantic (van Leeuwen 2003) is considered limited today due to outdated combinations and are not mentioned here.

Table 6.4. Randomized studies on agents of different classes as initial regimen for therapy-naïve patients.
Study 3rd agent Major results
Large well-powered studies
ACTG 5142(Riddler 2008)

EFV versus LPV/r

(250+253)

Less VF on EFV, severe AEs same (but more lipoatrophy on EFV)
ACTG 5202(Daar 2010)

EFV versus ATV/r

(929+928)

VF same, more severe AEs on EFV (in combination with ABC+3TC), but better lipid profile
ARTEN 5202(Soriano 2011)

NVP versus ATV/r

(376+193)

VF same, slightly more severe AEs and resistances with NVP
STARTMRK(Lennox 2010)

EFV versus RAL

(282+281)

VF same, more AEs
Smaller trials or trials in resource poor countries or in subgroups
ALTAIR(Puls 2010)

EFV versus ATV/r

(114+105)

VF same, AEs same (slightly less increase of peripheral fats with EFV)
KISS(Maggiolo 2009)

EFV versus ATV/r

(124+62)

VF same, AEs same
PHIDISA(Ratsela 2010)

EFV versus LPV/r

(888+883)

VF same, clinical endpoints same (South Africa <200 CD4 T cells/AIDS)
(Sierra-Madero 2010)

EFV versus LPV/r

(95+94)

Less VF under EFV than on LPVr, better lipid profile on EFV (Mexico, <200 CD4 T cells)
NEWART (De Jesus 2010)

NVP versus ATV/r

(75+77)

VF same, but lipids better with NVP
OCTANE II(McIntyre 2010)

NVP versus LPV/r

(249+251)

VF same, but more severe AEs with NVP (African women <200 CD4 T cells)
004(Marcowitz 2009)

EFV versus RAL

(38+160)

VF same, more AEs with EFV
Note: Different (partly randomized) NRTI backbones were utilized, in some cases there were other trial arms. VF= Virologic Failure, AE= Adverse Events. Note: The MERIT study with maraviroc is not mentioned here, as maraviroc is not licensed for first-line therapy.

In most of the trials, the antiviral potency of the regimens was comparable, measured by the number of patients with viral load below the limit of detection. In ACTG 5142, an advantage of efavirenz over lopinavir/r was observed after 96 weeks (12% more patients got to below 50 copies/ml). However, if ART failed, resistance was less frequent in the LPV/r arm and CD4 T cells increased more. The ACTG 5142 trial showed that NNRTIs were possibly more effective than boosted PIs, because they were better tolerated. Resistance, however, occurs faster on NNRTIs than on PIs, which is probably due to the low resistance barrier. This phenomenon was observed in trials such as FIRST, ARTEN and ACTG 5202 (Gardner 2008, Daar 2010, Soriano 2011).

These observations were confirmed in a systematic evaluation of 20 studies that included 7949 patients (see Table 6.5). All of the patients had been treated with either an NNRTI or a boosted PI, and had additionally received 3TC or FTC. Virologic failure was as frequent on NNRTIs as on PIs (4.9% versus 5.3% of patients, p=0.50). However, major differences were observed in patients with virologic failure whose genotypic resistance testing was successful. Mutations were significantly higher with NNRTIs. This applied for NRTI key mutations like the M184 and K65R, and also for other resistance mutations.

Table 6.5. Rates of resistance mutations at therapy failure on first regimens containing NNRTIs or PIs, in percentages (Gupta 2008).

NNRTIs

PIs

p

M184V

35.3  (29.3-41.6)

21.0 (14.4-28.8)

<0.001

K65R

5.3  (2.4-9.9)

0 (0-3.6)

0.01

Resistance to third agent (NNRTI or PI)

53.0  (46-60)

0.9 (0-6.2)

<0.001

Data on resistance development of the integrase inhibitor raltegravir in initial regimens is limited and long-term data lacking. However, studies testing raltegravir versus efavirenz, showed at least comparable efficacy with overall better tolerability over a period of approximately three years (Markowitz 2009, Lennox 2010).

Thus, the pros and cons for the different strategies continue, and controversy over the best first-line therapy persists. One should be warned against cross-trial comparisons, which are often used as marketing strategy to influence health providers of the effectiveness of a specific treatment (“we achieved over 90% tolerance rates in our study”). In a systematic evaluation of 10 large-scale randomized trials with 2341 therapy-naïve patients receiving AZT+3TC+efavirenz, the success rates (viral load in the ITT analysis <50/copies/ml at 48 weeks) ranged between 37% and 77%. This broad range was seen with use of the same combination in ART-naïve patients. Heterogeneous patient populations and study designs (definition of therapy failure), but also clinician experience and adherence may lead to variations (Hoffmann 2007).

Below, various strategies or primary therapies are discussed. These include:

  1. Two NRTIs plus an NNRTI
  2. Two NRTIs plus a PI
  3. Two NRTIs plus an integrase inhibitor
  4. Three or four NRTIs (triple-nuke, quadruple-nuke)
  5. Once-daily combinations
  6. Experimental combinations (nuke-sparing, intensive approaches)
  7. Problematic primary therapies to be avoided

1. Two NRTIs plus an NNRTI

NNRTIs have an equal, if not superior effect on surrogate markers compared to PI combinations. NNRTIs have performed well in numerous randomized studies: efavirenz-based regimens were superior to unboosted PIs such as indinavir or nelfinavir (Staszewski 1999, Robbins 2003) and at least equivalent to lopinavir/r (Riddler 2003), atazanavir (Daar 2010) or raltegravir (Lennox 2010). Nevirapine-containing regimens were mostly equivalent to atazanavir/r or lopinavir/r (McIntyre 2010, Soriano 2011).

Advantages of NNRTI regimens include the low pill burden and good long-term tolerability. In contrast to PIs, however, data with clinical endpoints is not available. Neither is there any long-term data or studies on severely immunocompromised patients. A disadvantage of NNRTI combinations is the rapid development of cross-resistance. This could result in failure, especially for highly viremic patients, although this has not been confirmed. Resistance upon virologic failure is generally more frequent on NNRTIs than on PIs (Gupta 2008, see above). Allergies are frequent on all NNRTIs. Hepatic adverse events requiring careful monitoring (nevirapine) but also central nervous system side effects and potential teratogenicity (efavirenz) should be considered. The 2NN trial showed no significant difference in efficacy between efavirenz and nevirapine in combination with d4T+3TC (van Leth 2004).

TDF+FTC plus efavirenz is one of the most frequently used combination at present and available as a single pill Atripla®. In the Gilead 934 Study and in a large Switch trial, TDF+FTC plus efavirenz was more effective than AZT+3TC plus efavirenz (Arribas 2008, Fischer 2010). It should be noted that in Europe, approval for Atripla® is stricter than in the US. Although the bioequivalence with each individual substance has been shown, the EMA restricts the use  of Atripla®. It is only approved for patients with virologic suppression under 50 copies/ml for at least three months on their current antiretroviral regimen. Furthermore, patients must not have experienced virologic failure with an earlier treatment combination or be known to have resistance to any of the three components in Atripla®. These slightly strange restrictions should be observed in Europe, as TDF+FTC (Truvada®) and efavirenz (Sustiva®) only require one more pill a day.

TDF+FTC plus nevirapine is also a frequently prescribed regimen. However, there is less data available than for efavirenz. Smaller trials observed an increased risk for therapy failure and for development of resistance, especially when viral load was high (Towner 2004, Lapadula 2008, Rey 2009). The large ARTEN trial also showed a slightly higher risk for resistances under TDF+FTC plus nevirapine, but an altogether comparable efficacy to TDF-FTC plus atazanavir/r (Soriano 2011). In favor of nevirapine are its good lipid profile and the excellent long-term tolerability, despite some risk for severe allergies and hepatotoxicity in the first few weeks.

TDF+3TC plus efavirenz was virologically equivalent to d4T+3TC plus efavirenz in the double blind, randomized Gilead 903 Study, although tolerability was significantly better (Gallant 2004). There are convincing long-term data out to more than 6 years (Cassetti 2007). However, the combination of TDF+3TC is seldom used today in Europe and the US, as there is no FDC available. Moreover, there is no reason to use 3TC instead of FTC.

ABC+3TC plus efavirenz (or nevirapine) is an alternative first-line therapy, if HLA testing to predict hypersensitivity to abacavir is available. The combination ABC+3TC plus efavirenz has been evaluated with success in numerous large trials such as CNA30024 (DeJesus 2004), ZODIAC (Moyle 2004) and ABCDE (Podzamczer 2006). More recent studies such as ACTG 5202 and ASSERT showed slightly less efficacy than on comparable regimens (Daar 2010, Post 2010). In ASSERT, less renal and bone side effects and were observed than with TDF+FTC (Post 2010, Stellbrink 2010). Data on ABC+3TC plus nevirapine are so far limited. An alternative to abacavir should be considered in patients with an increased risk for cardiovascular disease (Behrens 2010), although this has been questioned by a more recent FDA analysis (Ding 2011).

AZT+3TC plus efavirenz or nevirapine were among those regimens most frequently used and have been evaluated in numerous milestone trials (006, Combine, ACTG 384, 5095, 934). Side effects may occur during the first weeks. In the 934 Study, anemia and gastrointestinal problems occurred frequently in some cases, which significantly compromised the efficacy of AZT+3TC in contrast to TDF+FTC (Arribas 2008). Side effects such as increased lipids and lipoatrophy are significantly reduced by changing to TDF+FTC (Fischer 2010). Another disadvantage is the fact that with these combinations (including AZT), QD dosing is not possible. This regimen can only be recommended if there are good reasons not to use tenofovir or abacavir.

2. Two NRTIs plus a PI

The combination of two NRTIs plus one protease inhibitor is the only three-drug combination ART that is supported by efficacy data from randomized studies with clinical endpoints (Hammer 1997, Cameron 1998, Stellbrink 2000). Given the high resistance barrier and the robustness of these regimens, many experts still prefer to use these combinations today, particularly in advanced patients or those with high viral load. Resistance on boosted PIs is significantly less than from NNRTIs; PI/r resistance hardly exists (Gupta 2008). The slightly higher pill burden and frequent gastrointestinal side effects, which complicate compliance, are disadvantages of a PI-containing therapy. Often small factors are important when choosing the right PI, see Table 6.6.

Table 6.6. Frequently used PIs. Issues which may have an impact on treatment decision.

 

DRV/r

LPV/r

ATV/r

SQV/r

FPV/r

Pill number/day

3

4

2

6

4

Once daily dosing?

yes

yes

yes

no

 no (US: yes)

Intake with food?

Irrelevant

Irrelevant

yes

yes

Irrelevant

Important side  effects

Diarrhea (mild)

Diarrhea

Hyperbilirubin., icterus

Diarrhea (mild)

Diarrhea

Main study

ARTEMIS

Diverse

CASTLE

GEMINI

KLEAN

The following briefly describes the most common combinations:

TDF+FTC plus darunavir/r has been licenced for initial therapy since February 2009 and is one of the preferred first-line regimens in most guidelines. The combination proved at least as effective as TDF+FTC plus lopinavir/r in the ARTEMIS trial. With regard to tolerance it was even better (less diarrhea, less lipid changes) (Ortiz 2008). The effects remain stable out to 96 weeks (Mills 2009). Another advantage of this combination is the once-daily dosing. A disadvantage however for all boosted PIs is that ritonavir must be kept in the refrigerator. This changed in April 2010 with the introduction of ritonavir tablets.

TDF+FTC plus atazanavir/r was approved for first-line in 2008. In the CASTLE trial, atazanavir/r proved virologically equal to lopinavir/r, but with better lipids and similar tolerance (Molina 2010). Although a randomized study showed no difference between unboosted and boosted atazanavir (Malan 2008, Squires 2009), boosting with ritonavir is recommended. The main arguments in favour of this combination are the low number of pills and the good lipid profile. The major disadvantage is hyperbilirubinemia, which often manifests as harmless but disturbing icterus.

TDF+FTC or ABC+3TC plus lopinavir/r have been categorized in many guidelines as a preferred combination. However, after the results of CASTLE, ARTEMIS and ACTG 5142 (see above), lopinavir/r was recently down-graded in the US (by the DHSS) to an alternative regimen. More data is available for TDF+FTC as a backbone for lopinavir/r, although the HEAT study did not find significant differences compared to ABC+3TC (Smith 2008). Since 2009 lopinavir/r has also been licensed for once-daily use, after several studies had shown similar efficacy and tolerability (Molina 2007, Gathe 2009). However, there is some evidence that the potency of once-daily dosing is slightly less than BID (Ortiz 2008, Flexner 2010). Lopinavir/r lost its main advantage of not requiring cool storage compared to other boosted PIs, with the introduction of the Norvir® tablets in 2010.

ABC+3TC (or TDF+FTC) plus fosamprenavir/r: In the KLEAN study, this combination proved almost equal to ABC+3TC plus lopinavir/r in regard to both efficacy and tolerability. Better rates of diarrhea or cholesterol levels were, however, not achieved (Eron 2006). In the ALERT study, fosamprenavir/r was as effective as atazanavir/r, both combined with a TDF+FTC backbone (Smith 2006). In Europe, once daily use of fosamprenavir/r has not been licensed, although using a low booster of 100 mg ritonavir should be possible (Hicks 2009, Cohen 2010).

TDF+FTC plus saquinavir/r: Saquinavir was the first PI which showed a survival benefit (Stellbrink 2000). More data with saquinavir is available with AZT backbones than with TDF-containing backbones. In the relatively small GEMINI study saquinavir/r with a TDF+FTC backbone proved to be non-inferior to lopinavir/r (Walmsley 2009). The even smaller BASIC study showed that a once-daily dosing (1000/100) was comparable to atazanavir/r with regard to lipid profiles (Vrouenraetes 2009). The main disadvantage of saquinavir-based regimens is the approved twice-daily dosing and the high pill burden, which is why the combination is rarely used today.

3.Two NRTIs plus one integrase inhibitor

Raltegravir was licensed as the first integrase inhibitor for first-line treatment in 2009. Tolerance and efficacy are both excellent, although once-daily dosing is not possible or slightly weaker (Vispo 2010, Eron 2011) as for now, long-term data covering a period of over 3 years, especially regarding tolerability, are lacking. Indications appear when NNRTIs or PIs are less favorable for primary therapy, especially when interactions are expected.

TDF+FTC (TDF+3TC) plus raltegravir: The promising data of the Phase II study (Markowitz 2009) was confirmed in the large STARTMRK trial, in which raltegravir proved at least as effective as efavirenz (Lennox 2010). Viral load decreased more rapidly in the raltegravir arm and CD4 T cell counts increased. In addition, tolerance was better and effects lasted over 196 weeks (Gotuzzo 2010). It should be noted that data is available for raltegravir with TDF-based backbones while data for ABC+3TC or other backbones is still very limited. A pilot study with ABC+3TC plus raltegravir, however, showed no negative effects (Young 2010).

4. Three or four NRTIs – triple nuke or quadruple nuke

Triple or quadruple nuke therapies have several advantages: fewer interactions, no side effects typical of PIs or NNRTIs, and the fact that all other drug classes can be spared for later. The major disadvantage of triple nuke therapies is that they are virologically less potent than other combinations. While this may not be the case with quadruple nukes, the increasing knowledge of the mitochondrial toxicity of NRTIs makes pure nuke therapies less attractive.

AZT+3TC+ABC in a single tablet Trizivir® (BID) is the classic triple nuke therapy. Since ACTG 5095, Trizivir® is no longer equivalent (Gulick 2004) and clearly less effective than AZT+3TC plus efavirenz. This also applies for developing countries, where Trizivir® is still occasionally propagated (Munderi 2011).

AZT+3TC+TDF: We have had fairly good experience with this approach (Mauss 2005). Given the different resistance pathways of AZT and TDF, the thymidine analog seems to be protective against tenofovir-associated mutations (Rey 2006, see chapter on resistances). However, larger studies have not been conducted. The use of this combination has also met with some criticism (Maggiolo 2009).

AZT+3TC+ABC+TDF: Some studies have reported good responses and low rates of virologic failure on this quadruple nuke therapy (Moyle 2006, Elion 2006, Gulick 2007, Ferrer 2008). However, these studies were not powered to demonstrate equivalence to other combination regimens. In two randomized studies, discontinuation rates were high, due to adverse events (Mallolas 2008, Puls 2010). In the ALTAIR study, it proved less effective than the standard ART regimen (Puls 2010).The long-term toxicity and efficacy of these combinations is still unknown.

TDF+3TC+ABC/ddI should be avoided (Jemsek 2004, Gallant 2005, Khanlou 2005). In up to 49% of patients, early virologic treatment failure has been seen, probably due to a low genetic resistance barrier (Landman 2005). This is also true for treatment-experienced patients who want to simplify their therapy (Hoogewerf 2003, Perez-Elias 2005).

Conclusion: Pure NRTI combinations are not recommendable for first-line therapy. Triple nuke is poorer in comparison to regimens of at least two classes and the results of some of the single-class combinations are truly not good. Data on quadruple nukes is too limited. However, triple and quadruple nuke therapy remains under consideration for maintenance therapy (see Chapter 7).

5. Once-daily combinations

Many drugs have been licensed for QD administration (once-daily, Table 6.7). Some experts still fear that once-daily dosing is unfavorable with respect to the theoretical development of resistance. If one dose is forgotten, 24 hours without treatment goes by. These regimens may therefore be less forgiving, particularly if there are problems with compliance.

It has still not been confirmed that once-daily regimens really improve compliance. A recent meta-analysis, however, suggests  an improvement  (Parienti 2009).

Table 6.7. Antiretroviral drugs and their usage in first-line once-daily regimens.
Trade name Abbrev.

Once-Daily?

Comment
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Emtriva® FTC

Yes

Epivir® 3TC

Yes

Retrovir® AZT

No

QD definitively not possible
Videx® ddI

Yes

Must be taken on an empty stomach
Viread® TDF

Yes

Zerit® d4T

No

D4T-XP is no longer coming
Ziagen® ABC

Yes

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Intelence® ETV

No

QD not possible, no approval for first-line
Rescriptor® DLV

No

QD not possible, no approval for first-line
Sustiva®, Stocrin® EFV

Yes

Viramune® NVP

Probably

approval for QD NVP “ext’d release”
Protease inhibitors (PIs)
Aptivus® TPV/r

No

QD not possible, no approval for first-line
Crixivan® IDV/r

No

Limited data
Darunavir® DRV/r

Yes

Invirase® SQV/r

Possibly

Studies ongoing
Kaletra® LPV/r

Yes

Only for treatment experienced patients
Reyataz® ATV/r

Yes

US: Unboosted ATV also approved
Telzir/Lexiva® FPV/r

Yes

QD licenced in US but not in Europe
Viracept® NFV

No

Limited data
Entry inhibitors, integrase inhibitors
Celsentri®, Selzentry® MVC

No

No approval for first-line
Fuzeon® T-20

No

QD not possible, no approval for first-line
Isentress® RAL

No

Probably not possible
Fixed combinations
Atripla® TDF+FTC+EFV

Yes

Restricted first-line approval in Europe
Combivir® AZT+3TC

No

QD not possible due to AZT
Kivexa®, Epzicom® 3TC+ABC

Yes

Trizivir® AZT+3TC+ABC

No

QD not possible due to AZT
Truvada® TDF+FTC

Yes

Tolerability of some agents could become worse due to higher peak levels. In the 418-study, QD lopinavir showed more incidence of diarrhea than the twice daily dosage (Molina 2007). Once daily does not only influence the peak levels – but trough levels decrease, especially with boosted PIs, due to the longer intervals between the individual doses. This can be of relevance when viral load is high (Flexner 2009) and with treatment-experienced patients (la Porte 2005). This was true also with raltegravir, which is why raltegravir should not be administered once-daily (Vespo 2010, Eron 2011).

6. Experimental combinations

Antiretroviral therapies need to be more effective and tolerable. Although integrase and entry inhibitors offer new options, investigation on classic ART is still ongoing. Two approaches have attracted great interest: combinations without any NRTIs (nuke-sparing or monotherapies), and so-called induction therapies. Both approaches will be discussed below.

Nuke-sparing

All classical ART regimens have to date included a backbone consisting of two nucleoside or nucleotide analogs. This is mainly historical: nucleoside analogs were the first drugs on the market, and by the time NNRTIs and PIs were under development, treatment with two nucleoside analogs was standard. With growing knowledge of the mitochondrial toxicity of nucleoside analogs, nuke sparing, i.e., omission of NRTIs, is increasingly being investigated, even for first-line therapy. Nuke-sparing with pretreated patients will be discussed later on in the book (see When to Switch).

Data for nuke-sparing as first-line is limited. As shown in Table 6.8, mostly smaller studies have been conducted so far.

NNRTI plus PI: ACTG 5142 was the first large study providing convincing evidence for the nuke-sparing strategy (Riddler 2008, see above). This study showed that a combination of lopinavir/r and efavirenz was not inferior to two NRTIs with either lopinavir/r or efavirenz. A randomized African trial showed that different nuke-sparing regimens (different NNRTIs plus PIs) were inferior to standard ART regimens (Duvivier 2008). In contrast, two other small, randomized studies found no significant difference between nuke-sparing and standard regimens (Harris 2005, Cameron 2005). It is still unclear whether side effects really improve with nuke-sparing regimens. A sub-study of HIVNAT 009 reported that lipoatrophy resolved, and that visceral fat and subcutaneous limb fat increased (Boyd 2005). In CTN 177 nuke-sparing regimens had a favorable effect on lactate levels (Harris 2005). In ACTG 5142 rates of lipoatrophy were lower in the nuke sparing arm (Haubrich 2009). However, adverse events in total were not reduced and dyslipidemia was observed even more frequently (Riddler 2008).

Pilot trials have also shown poor response rates for a double PI, which is why this nuke-sparing approach will probably not be further investigated for now (Ulbricht 2008, van der Lugt 2008, Landman 2009).

INI/CCR5A plus PI: Many studies are ongoing, especially with raltegravir and maraviroc, boosted with one PI, respectively: raltegravir is not only tested with lopinavir/r or atazanavir/r (PROGRESS study, CCTG 589), but also with darunavir/r in treatment naïve patients (RALDAR, NEAT 001). Maraviroc is also combined with darunavir/r. Is this the future? What does the data say?

The PROGRESS study showed a more rapid and impressive reduction of viral load already after 8 weeks, than with the classic combination of TDF+FTC plus lopinavir/r. After 48 weeks, antiviral effect was comparable (Reynes 2010). However, there have been some setbacks. In ACTG 5262, a one-arm study with darunavir/r plus raltegravir, many patients had not achieved a viral load under detection level at week 48 and 5 out of 112 patients developed resistance to raltegravir (Taiwo 2011). Strikingly, these patients already showed several resistance mutations at baseline and there was some doubt whether all patients really were treatment-naïve. However, the SPARTAN study confirmed these results, where 4/63 (6.3%) patients developed raltegravir resistances on a combination of raltegravir and unboosted atazanavir (300 mg BD). On account of these results, the study was discontinued prematurely. Unfortunately, PK data of patients showing virological failure was not available, which could have explained the therapy failure. Raltegravir, however, probably reduces the level of atazanavir (Zhu 2010). A striking observation in SPARTAN was the high rate of severe hyperbilirubinemia (grade 4), with 21% under atazanavir plus raltegravir, compared to no cases in the TDF+FTC plus atazanavir/r (Kozal 2010). This combination can therefore not be recommended in this form. In view of the rather low resistance barrier, a boosted PI as a partner substance seems necessary.

 

Table 6.8. Prospective studies on nuke-sparing regimens in treatment-naive patients and patients with little prior treatment experience (intent-to-treat analyses).
 

n (naive)

Combination          (Study) Percentage <50 copies/ml
NNRTI + PI
Staszewski 1999

148 (126)*

EFV+IDV           (006-Study) 47% at 48 weeks
Boyd 2003

61 (0)*

EFV+IDV/r     (HIVNAT 009) 69% at 96 weeks
Allavena 2005

86 (65)*

EFV+LPV/r                 (BIKS) 73% at 48 weeks (<400)
Riddler 2008

253 (253)

EFV+LPV/r      (ACTG 5142) 83% at 96 weeks
Harris 2009

14 (14)

NVP+LPV/r          (CTN 177) 78% at 48 weeks
Ward 2006

63 (63)

EFV+ATV/r          (BMS 121) 63% at 48 weeks
INI/CCR5 + PI
Kozal 2010

63 (63)

RAL+ATV              (Spartan) 81% at 24 weeks
Mills 2010

60 (60)

MVC+ATV/r       (A4001078) 89% at 24 weeks
Nozza 2010

7 (7)

MVC+LPV/r 100% at 24 weeks
Reynes 2010

103 (103)

RAL+LPV/r     (PROGRESS) 83% at 48 weeks
Taiwo 2011

112 (112)

RAL+DRV/r      (ACTG 5262) 26% VF at 48 weeks
*Patients all PI-naïve. VF=Virologic Failure

Promising first results were shown with the combination atazanavir/r and low dosed maraviroc (Mills 2010). Resistances were not observed in this study; however, larger studies with maraviroc and darunavir/r are in planning. The combination of maraviroc and a boosted PI could also be important, as the tropism test does not always show valid results. There is also a risk for patients starting an insufficient monotherapy if non-R5-viruses are not recognized.

With regard to the data available, it is still premature to be able to recommend nuke-sparing as an equal alternative in its own right.

Monotherapy, alternating therapy

Can it get any easier? Several studies introduced a very avant-garde concept in the summer of 2003: monotherapy with boosted PIs. With respect to the high resistance barrier of boosted PIs, success was considerable (Gathe 2009). Lipoatrophy can be avoided (Kolta 2011).However, in many studies, low-level viremia was found to be more frequent on monotherapies. In the MONARK study, only 64% (compared to 75% on AZT+3TC+lopinavir/r) of the patients on lopinavir/r achieved a viral load of less than 50 copies/ml at 48 weeks (Delfraissy 2008). At 96 weeks it was only 47% (Ghosn 2009). Darunavir/r also started to show weaker effects in a small pilot study (Patterson 2009). According to one overview, the overall efficacy of monotherapy is slightly less effective to standard ART (Bierman 2009). This strategy is not recommended for treatment-naïve patients. In view of the constantly growing choice of well-tolerated combinations, it is difficult to find good arguments for monotherapy other than cost aspects.

Another approach is alternating therapy, which involves changing treatment every few weeks. In the SWATCH Study (Martinez-Picado 2003) a total of 161 patients were randomized to a regimen of d4T+ddI+efavirenz or AZT+3TC+nelfinavir. A third arm changed between the two regimens every three months when the viral load was below the level of detection. After 48 weeks, virologic failure in the alternating arm was significantly reduced. There was no difference for any other parameters (CD4 T cells, side effects, adherence, and quality of life). Considering the fact that several therapies are well-tolerated, alternating strategies, which can be very confusing for the patient, have never gained much attraction.

Induction with 4 or 5 drugs

Some experts speculate on whether more intensive approaches than conventional triple combinations are necessary for patients with high viral load. Because of fear of rapid development of resistance, some physicians give initial treatment with an induction of four or even five drugs, and then simplify to a triple combination once the viral load has dropped below the level of detection.

This theoretical concept has not yet been validated, and is based on hypotheses or smaller proof-of-concept studies (Ramratnam 2004) in which it has been shown that the viral load falls faster under intensive combinations than under standard therapies with three active drugs. Approaches in which multiple individual drugs (usually nucleoside analogs) are given have to be distinguished from approaches in which three instead of two classes of drugs are used.

Multiple individual drugs: Current data indicates that there is no benefit to using this strategy. Giving two PIs or two NNRTIs instead of one sometimes produces even negative results (Katzenstein 2000, van Leth 2004). There is also no evidence in favor of giving three instead of two NRTIs (Staszewski 2003, Orkin 2004, Mallolas 2008, Hammer 2010). In ACTG 5095 with 765 patients, there was clearly no difference between Combivir® plus efavirenz and Trizivir® plus efavirenz, not even when the starting viral load was higher, or with regard to resistance (Gulick 2005).

More drug classes: The data on whether to use three or two drug classes is less clear. However large studies on this subject, such as ACTG 388 (Fischl 2003), ACTG 384 (Robbins 2003, Schafer 2003), INITIO (Yeni 2006) or FIRST (May Arthur 2006) were conducted with old combinations with nelfinavir as the main PI and ddI+d4T as the backbone. Therefore, validity of these studies is limited. A more recent randomized study with additional doses of T-20 in late presenters showed some effect on the viral load after 24 weeks, but these results were not sustained through week 48 (Joly 2010).

In summary, it is questionable whether intensification of therapy leads to any improvement at all and produces anything more than toxicity and cost. The studies above indicate that supposed improved efficacy (not shown in many trials) is counterbalanced by more side effects. Indeed, there is the risk of scaring patients away with the higher number of pills and side effects. It is unclear whether and in which patients such intensification of therapy is useful, and which drugs would be optimal.

7. Suboptimal first-line therapies

Combinations generally considered to be suboptimal include all forms of mono- and dual therapy, especially two nucleoside analogs. Even one nucleoside analog plus one NNRTI is not good as shown by the INCAS Trial (Montaner 1998). When using NRTIs, it is important to make sure that they are not competing for the same pocket. The thymidine analogs AZT and d4T are even antagonistic (Pollard 2002). According to a warning letter by the company BMS in March 2011, d4T should generally be avoided (not only in first-line).

Full dose ritonavir can be rejected as an active agent, as the tolerability is very poor. There is no longer a reason to use ddI, indinavir or nelfinavir in a first-line regimen. Some drugs, such as T-20, etravirine, and tipranavir are not licensed for use in primary therapy. Drugs such as ddC (HIVID®), saquinavir-SGC (Fortovase®) and amprenavir (Agenerase®) have been taken off the market.

NNRTI combinations act non-competitively at the same site, and furthermore all can cause a rash, making differential diagnosis difficult. Efavirenz levels seem to be lowered considerably in combination with nevirapine (Veldkamp 2001). In the wake of the 2NN Study, it seems clear that the combination of efavirenz and nevirapine should be avoided. The study arm with this combination fared worse than the other arms, mainly due to toxicity (Van Leth 2004). NNRTIs should also not be combined with raltegravir alone – the resistance barrier is probably too low.

TDF in a triple nuke combination should not be administered. Many studies have reported poor response rates, particularly in combination with ABC+3TC (Hoogewerf 2003, Jemsek 2004, Khanlou 2005, Gallant 2005) (see Triple Nukes).

TDF+ddI: at least five trials looking at TDF+ddI plus an NNRTI resulted in a high failure rate, and some were stopped prematurely (Leon 2005, Podzamczer 2005, Maitland 2005, van Lunzen 2005, Torti 2005). BMS even issued a warning letter concerning TDF+ddI. The combination of TDF+ddI no longer has a place in antiretroviral therapy.

Starting gradually: All drugs should be started simultaneously. Highly significant differences were shown between patients who had received three drugs immediately compared to those patients who were started on only two drugs (Gulick 1998, Ait-Khaled 2002). This is significant in the long-term. A large cohort study showed that the risk of virologic failure was doubled even years later if dual therapy had been the starting regimen, even for as little as a few weeks (Phillips 2002). Initiating triple therapy gradually, as is sometimes practiced due to concerns of side effects, is wrong and dangerous.

Avoidable mistakes in first-line therapy

  • Mono- or dual therapy (except in controlled trials) as well as a gradual introduction of therapy – always start with a complete ART regimen
  • Starting at a lowered dose (except for nevirapine)
  • T-20, delavirdine, tipranavir, etravirine, maraviroc (not licensed for primary therapy in Europe)
  • ddC (HIVID®), SQV-SGC (Fortovase®), amprenavir (Agenerase®) – distribution has been stopped
  • Ritonavir (not tolerated – only for use as low-dose booster)
  • AZT+d4T and 3TC+FTC (antagonistic effects)
  • D4T in general without a good reason, if there is any
  • TDF+ddI (diverse reasons), d4T+ddI (toxicities)
  • TDF in triple-nuke therapy (especially without thymidine analogs)
  • Simultaneous introduction of ABC and NNRTIs without prior HLA testing (allergy potential)
  • Efavirenz+nevirapine (too toxic)
  • Efavirenz or nevirapine+raltegravir (low resistance barrier)

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