BHIVA draft adult antiretroviral treatment guidelines: What to start with

3.0 What to start with

3.1 Choices of initial therapy

There is overwhelming evidence from cohort studies that the very dramatic fall in AIDS-related mortality and frequency of AIDS events seen in the developed world over the last three years coincides with the introduction of highly active antiretroviral therapy (HAART) [57]. The choice of any HAART regimen should be individualised in order to maximise adherence, and particular attention should be paid to potency, tolerability, potential toxicity and likely drug-drug interactions. Since the first-line option may limit future choices in the event of virological failure, it should be selected with extreme care. Table 4 summarises the pros and cons of available options.

3.2 Which HAART regimen is best?

There have been no definitive clinical controlled trials to demonstrate superiority of any one potent (HAART) strategy (ie: PI first, NNRTI first, 3 nucleoside analogues first) used as initial therapy over another. Patients should be informed about and encouraged to participate in any such trials. Several regimens will be discussed below and the advantages and disadvantages of each will be assessed. For a detailed discussion of the issues surrounding protease inhibitor (PI) use, see section 4.

3.2.1 Two nucleoside analogues plus a protease inhibitor

A dramatic decline in clinical progression and HIV-related deaths followed the introduction of the protease inhibitor (PI) class of antiretrovirals (Table 5). These agents have shown clinical and surrogate marker efficacy in clinical practice. Sustained suppression of plasma HIV-1 RNA levels for more than 4 years has been seen in some patients within the Merck 035 study taking indinavir and two nucleoside analogues [58]. ACTG 320 was a clinical endpoint study which demonstrated long-term virological suppresion and improved clinical outcome in patients taking ZDV/3TC/indinavir [32]. Improvement in clinical outcome has also been seen in studies with combinations of ritonavir added to background antriretroviral therapy (containing NAs) in late disease [59]. The hard-gel formulation of saquinavir has also shown clinical benefit when used in combination [60], but is not recommended as the sole PI in a HAART regimen because of its poor bioavailability. The dosing of PIs within HAART regimens remains to be exactly determined. Ritonavir boosted PI have simplified PI regimens.

There has now been demonstration in surrogate marker studies of the superiority of lopinavir/ritonavir combination over nelfinavir.

Table 4 – Choices of initial therapy: summary of recommendations

Footnotes: (1) Hard-gel saquinavir should not be used as the sole PI. There are fewer data concerning use of saquinavir soft-gel in this context than for other PIs.

(2) Primary reason for combining PIs is to improve pharmacokinetics. Suggested regimens: low-dose ritonavir with hard gel or soft gel saquinavir, lopinavir or indinavir.

(3) Recommended NNRTIs are efavirenz or nevirapine. In one controlled trial, efavirenz was as effective in patients with viral loads >100,000 copies/ml as in those with

Table 5 Currently available protease inhibitors used as a single protease inhibitor

Footnotes: (1) Dose currently unlicensed

3.2.2 Combinations of protease inhibitors

Combinations of PIs in clinical use are: (i) ritonavir/saquinavir, (ii) ritonavir/indinavir and (iii) ritonavir/lopinavir. There is now accumulating data on these combinations and they appear to have advantages over agents used alone. Firstly, they have improved 24-hour pharmacokinetics, with higher trough levels and reduced fluctuations in plasma concentration over time. This allows lower doses to be taken at longer intervals, ie: twice instead of three times a day, and without dietary restrictions. Secondly, the improved pharmacokinetics should assist adherence. Thirdly, the additive or synergistic antiviral effects of PIs in combination may improved potency relative to a regimen including a single PI. One study has now shown that ritonavir/lopinavir is more effective than nelfinavir alone [61]. This, however, may be related to adherence rather than intrinsic antiviral potency. Another study showed no statistical difference in viral load suppression between combinations containing either nelfinavir or soft-gel saquinavir as the sole PI and those containing a combination of both [62].

Possible disadvantages of combining PIs are an increased risk of lipodystrophy and severe lipid abnormalities. Unfavourable pharmacokinetic interactions between the PIs or with other drugs may also occur.

Table 6 Currently used boosted PIs

¹ Dose currently unlicensed

² Pharmacokinetics for ritonavir/saquinavir SGC are equivalent for HGC as yet unpublished

3.2.3 Two nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor

These drug combinations have not been as well evaluated as PI combination in controlled trials using clinical endpoints [63]. A number of studies using these combinations have however shown impressive surrogate marker results. Direct data comparing the two currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine in terms of their effects on surrogate markers and safety are awaited. The choice between them is therefore likely to be based on these results.

Table 7 Currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs

Footnotes: (1) At night (2) The initial dose is 200 mg/day for 2 weeks, increasing to 400 mg/day.

Efavirenz

Impressive surrogate marker results have been obtained using efavirenz with two nucleoside analogues (ZDV and lamivudine [3TC]). In a randomised open-label study, this combination was compared with ZDV, 3TC and indinavir and showed either no difference or superior surrogate marker endpoints up to 104 weeks of follow up when analysed in a variety of ways (including intention to treat and on treatment analysis)[36].

The major drawback of this study was the high discontinuation rate in both arms. Thus by 48 weeks, 35% of the indinavir group and 25% of the efavirenz group had discontinued, this along with the open nature of the study may have biased the intention-to-treat analysis in favour of efavirenz. These discontinuation rates probably mimic what is seen in clinical practice. One of the chief advantages of an efavirenz-containing regimen is the once daily dosing of efavirenz, which may improve adherence. This is made possible by its long plasma half-life, which ensures that drug levels far exceed the IC90 (the concentration, determined in vitro, required to inhibit 90% of viral growth) throughout the day. This advantage may become a problem on stopping combinations with efavirenz; the long half-life of efavirenz, in comparison to some nucleoside analogues, means the drug may remain in the plasma for several days effectively exposing the patient to monotherapy and the associated risk of drug resistance.

The major side effect is dysphoria; manifestations include vivid dreams, depression, drowsiness and, in some, insomnia. This is usually self-limiting and it is unusual for patients to have to discontinue the drug because of it. Although rashes can occur, severe rashes with efavirenz are unusual. Lipid abnormalities, mainly rises in cholesterol above baseline values, have been observed in patients on efavirenz-containing combinations[64]. Efavirenz appears to be potent when used in patients with high viral titres (>100,000 copies/ml). As efavirenz may be teratogenic, women of child-bearing age should be warned of the potential risks if they become pregnant while taking this drug.

Nevirapine

Nevirapine with ZDV/didanosine (ddI) has been compared with ZDV/ddI alone in antiretroviral-naïve patients[65]. This study, which led to the licensing of nevirapine, showed superior HIV-1 RNA suppression at 48 weeks in the triple-therapy arm. Virological and immunological data are also available from a head-to-head comparison of nevirapine with a PI (indinavir) in combination with ddI and stavudine (d4T), with most of the data extending to 48 weeks (the Atlantic study[66]).

Nevirapine is currently used twice a day, but the pharmacokinetics indicate that once a day may be reasonable. Major side effects of nevirapine are rash, which occasionally manifests as Stevens-Johnson syndrome, and hepatitis, both of which can be fatal. Whether the drug rash with nevirapine can be reduced by the co-administration of steroids[67] or antihistamines remains to be proven in prospective clinical trials.

Advantages and disadvantages of NNRTIs

The side-effect profile of all the NNRTIs appears to be more favourable than that of PIs. This fact, coupled with their good pharmacokinetic properties and potential ease of adherence, is the major reason why many clinicians may chooe to use nucleoside analogues and an NNRTI as first-line therapy. A major disadvantage of the use of NNRTIs as part of such a regimen is that a single mutation in the reverse transcriptase gene can produce a virus with markedly reduced sensitivity, which probably extends to all members of the class[70].

Studies showing continuing success of HAART regimens in the long term are particularly important, but as yet there are very few data for patients on NNRTIs. For example, patients on PI-containing regimens who experience virological failure may maintain a stable or rising CD4 count with low-level plasma viraemia for long periods of time and a slow rate of clinical progression[71]. Whether the same will hold true for NNRTI-based regimens remains to be seen.

3.2.4 Three nucleoside analogues

Preliminary 48-week data from the Atlantic study showed no significant difference in viral load suppression (to below the 50 copies/ml threshold) for the triple NA arm (d4T/ddI/3TC) compared with the other two arms (d4T/ddI/nevirapine or d4T/ddI/indinavir) by intention-to-treat or on-treatment analysis[66]. A post hoc analysis showed that the triple NA arm did not suppress viral load to undetectable (

Studies indicate that the combination of abacavir (a guanosine analogue and inhibitor of reverse transcriptase) with two NAs is capable to producing long-term suppression of virus for up to 72 weeks[74]. Experience with triple NA combinations is more limited but two trials have now been reported; the first, a double-blind placebo-controlled study (CNA 3005 study) of AZT/3TC/abacavir compared with AZT/3TC/indinavir showed no significant difference in viral load suppression for the AZT/3TC/abacavir arm when compared to the AZT/3TC/indinavir arm. However, in a subgroup analysis those patients with high viral loads did have a better response in the indinavir arm than the abacavir arm. This latter study was a double blind placebo controlled trial with a high pill burden. When a similar study was repeated in an open fashion this difference was not apparent suggesting equal importance of adherence and potency.

Advantages and disadvantages of NAs

The major advantages of triple NA regimens are the simpler regimen, good tolerability, a relative lack of drug-drug interactions and a low incidence of side effects. The exception to this is abacavir hypersensitivity, a multiple system disorder often presenting with fever and rash, which occurs in up to 3% of patients. Re-challenging affected individuals has resulted in severe toxicity and death on occasion[75]. Therefore, the use of abacavir requires careful physician and patient education to avoid continuing or restarting therapy if such reactions occur.

The other potential advantages of triple NA therapy regimen are that virological failure will not be associated with the development of resistance to the other two currently available classes of drugs (NNRTIs and PIs). The negative side of this is the potential difficulty of finding further regimens containing new NAs for individuals who experience failure of their first-line therapy, because of overlapping toxicity or resistance profiles.

3.3 Recommendations for initial therapy

Insufficient data are available to make a definite recommendation as to initial treatment. Initial therapy must be individualised for each patient and the risks and benefits of the treatment considered including toxicity, adherence, resistance, immunological benefit, long-term safety, clinical trial data and stage of disease. Many clinicians now favour a NNRTI-based regimen for initial therapy reserving PIs for later use. 3NAs are usually limited to patients perceived to have major adherence concerns.

3.3.1 Choice of nucleoside analogue backbone for initial therapy

The choice of which NAs to use together is governed by overlapping toxicity, for example d4T/zalcitabine. ZDV/d4T are not used together as they share a common phosphorylation pathway for intracellular activation and one small study has shown a deleterious effect on CD4 counts when the latter combination was used[76]. Primary drug resistance, especially to ZDV, may affect the choice of initial NAs. This may be of particular relevance when considering a combination of ZDV with 3TC or an NNRTI, because of the relative ease with which resistant mutants are acquired. Although abacavir has been used most often in triple NA combinations, it may also be used in a ‘nucleoside analogue backbone’.

Nucleoside analogue toxicity

NA usage has been associated with numerous toxicities including lactic acidosis and hepatic steatosis, both of which have been linked to inhibition of mitochondrial DNA synthesis[77]. Lactic acidosis is often fatal. It can start insidiously, with nausea, weight loss, bloating and abdominal pain. In its full blown form, it may closely resemble Gram-negative sepsis. Treatment with agents to improve mitochondrial function, such as carnitine, riboflavin and DCA have been suggested[78], without any clear evidence of benefit. The prevalence of this condition is unknow, but since it was not apparent in most of the large clinical controlled trials of NA therapy, it is likely to be rare or to occur only after prolonged use.