Indirect evidence that the simultaneous discontinuation of unbalanced regimens may lead to resistance derives from case reports [5,48,49] and trials assessing structured treatment interruption (STI) (Table 2). In one report  a Caucasian man simultaneously discontinued a regimen (stavudine/lamivudine/nevirapine) because of hepatotoxicity. A subsequent regimen in which efavirenz replaced nevirapine was also stopped simultaneously. Genotyping subsequently confirmed the acquisition of the K103N mutation conferring broad non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. In the DART trial, plasma nevirapine concentrations were determined in 18 African adults discontinuing a nevirapine-based regimen. In that study there was a staggered stop (7 days). A conservative median plasma half-life of 39 h was estimated, and nevirapine concentrations were below the therapeutic range by one week . It is important to note that after a single dose of nevirapine, half-lives of 60 h or more have been observed [27,68]. There is therefore particular vulnerability to developing resistance in women given single dose nevirapine for the prevention of mother-to-child transmission [69–71]. The most likely reason for the difference in half-life (i.e. single dose versus multiple dose) is the autoinduction of nevirapine during chronic therapy, leading to a shortened half-life . When a 40-year-old African woman simultaneously stopped efavirenz, tenofovir, lamivudine and didanosine  her viral load (previously < 50 copies/ml) became detectable at 12 weeks (with wild type and the M230L/M mutation) and therapeutic plasma efavirenz concentrations were still present 8 weeks after stopping therapy.
Furthermore, most other STI studies have reported resistance emerging in the stopping arm of the study, with resistance levels as high as 45% (Table 2) [55,56,63].
STI studies also provide important information on the time to virological rebound after stopping, as this will influence resistance development. Although somewhat variable, viral rebound is usually rapid and exponential, with an HIV doubling time of approximately one and a half days. The average patient will have detectable virus present by 2 weeks, whereas almost all patients will have a high viral load by 4 weeks . Importantly, STI studies usually only enrol patients already fully suppressed
The ‘simultaneous stop’ may, however, be problematical when using longer half-life NNRTIs with short half-life NRTIs. Here the imbalance in half-lives is considerable. As nevirapine and efavirenz can persist at resistance-inducing concentrations for 2 weeks or more Fig. 1a [3,5,27,52], here the ‘simultaneous stop’ strategy is not advisable.
More problematical is stopping regimens containing longer half-life NRTI/NtRTI (i.e. emtricitabine and tenofovir) in combination with boosted protease inhibitors. This may lead to functional dual (Fig. 1c) or single (Fig. 1a) agent therapy if these agents are stopped together. In this situation, a different method of stopping may be more appropriate. When longer half-life NRTI/NtRTI are combined with nevirapine or efavirenz the matching of half-lives may support a simultaneous stop (Fig. 1d). We recognize that individual variation in drug metabolism  means that matching half-lives of all agents in the regimen is difficult. Clinical data are required to determine whether the simultaneous stopping of these agents will lead to resistance. This is important as fixed dose combination tablets become available .
In attempting to overcome the potential for resistance development with nevirapine or efavirenz and short half-life drugs, some guidelines suggest a ‘staggered stop’ . Here the long half-life drug is discontinued before stopping the other agents in the regimen. Three days were initially suggested, but then at least 5 days were recommended . Lyons and colleagues  reported that for some individuals 5 days appeared too short. The correct duration still remains a matter of opinion. We recommend that nevirapine (after multiple doses) should be stopped at least 7 days (perhaps even 2 weeks) before other shorter half-life drugs, or a different stopping strategy should be employed. Fidler et al.  showed that when stopping efavirenz 5–7 days before a predominantly zidovudine/lamivudine-containing regimen, no NNRTI resistance was documented at week 4 after stopping treatment. Our own data , and that of others [52,79] have demonstrated that in some individuals the half-life of efavirenz can be greater than 100 h, and efavirenz concentrations can persist at resistance-selecting concentrations for 2 weeks or more. There are clearly ethnic differences in drug handling so it may be more appropriate to stop efavirenz at least 2 weeks before other shorter half-life drugs, or adopt a different stopping strategy (Fig. 1e).
The ‘staggered stop’ approach is problematical if another agent in the regimen has a long half-life, e.g. efavirenz, tenofovir, or lamivudine. In that situation, if efavirenz was stopped 2 weeks before the other two agents, the shorter half-life of lamivudine relative to tenofovir would potentially give functional tenofovir monotherapy.
In this strategy the drug with the longest half-life is exchanged for a drug with a higher genetic barrier to resistance and a shorter half-life (e.g. lopinavir/ritonavir) for a period of time before the other agents and the new agent are stopped simultaneously (Fig. 1e). The advantage is that continued viral suppression is likely as the discontinued drug passes through the zone of resistance selection. Four weeks is probably advisable with this strategy to maintain viral suppression. The extended period will allow clearance of the NNRTI at the time of stopping other drugs. This method is likely to work when NNRTI are combined with the shorter-acting NRTI. Nevertheless, it may still be problematical with long half-life NRTI/NtRTI, i.e. functional monotherapy with either tenofovir or emicitrabine.
In an attempt to provide a universal stopping strategy, we are currently investigating the ‘protected stop’ (Fig. 1f), in which single agent lopinavir/ritonavir is given on the day patients stop all of the other ART agents. The regimen then continues for 4 weeks before stopping. The rationale comes from single agent lopinavir/ritonavir studies in which maintaining viral suppression was achieved with the minimal development of resistance [80,81]. The potential for resistance developing in the short time of single agent therapy is small, thus preserving future treatment options. Clinical data are, however, required before this can be recommended as a standard strategy.
Sometimes stopping ART will be unplanned and will be the result of unpredictable circumstances such as emergency surgery, intercurrent illness, or severe drug toxicity. Clearly, the overall safety of the patient is foremost over the need to preserve future treatment options. Generally, stopping all the drugs simultaneously would be recommended; however, there may be differences according to the situation:
We recommend stopping all agents simultaneously irrespective of the drug half-life.
With balanced half-life drugs that do not require food for absorption, a simultaneous stop is advised with recommencement of the same regimen as soon as possible.
If the patient is allowed water then these drugs may be continued if it is anticipated that drug absorption can occur. If the drug requires food for optimal absorption and all components have similar half-lives, then temporary discontinuation of all drugs simultaneously is warranted, with recommencement of the same regimen as soon as the patient can resume food.
Either a simultaneous stop or a limited staggered stop could be considered, depending upon the severity of the illness. The ‘exchange stop’ or ‘protected stop’ are probably best avoided as it would mean starting a new drug of which the patient has had no previous experience in an emergency situation.
Some women receive ART in pregnancy to prevent mother-to-child transmission, but may not require therapy for their own health. If the regimen taken by the mother does not lend itself to simultaneous stopping, deferring the stop until after the mother and baby have established a stable routine may be preferable. This is only advisable if it is anticipated that the mother will take therapy until a planned stop date is agreed.
If patients are hepatitis B surface antigen or e antigen positive, then discontinuation of these agents may lead to an exacerbation of hepatitis or a ‘hepatitic flare’ . These patients require close monitoring. Some suggest replacing the agents with activity against both HIV and hepatitis with drugs with a predominantly hepatitis B activity, i.e. adefovir, entecavir or telbivudine. In such cases expert opinion should be sought. It would not be recommended to continue lamivudine/emicitrabine or tenofovir alone for their antihepatitis B activity because of the risk of selecting HIV-resistant variants .
Whatever the reasons for stopping ART, pharmacological and virological issues must be considered in order for a clinician to give guidance. Understanding the pharmacokinetics of each drug is critical, because there is the potential for functional monotherapy if drugs with different half-lives are stopped simultaneously. Although there are few prospective clinical trial data to guide clinicians on how best to stop ART, there are clearly different strategies.
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