Many people respond well to antiretroviral therapy in terms of viral suppression or CD4 cell count rebound. However, toxicity in the form of serious side-effects, or concerns about ongoing adherence, may lead people to want to change from their current regimen.

Toxicity is the most common reason for stopping the first HAART regimen prescribed; an Italian study found that 21% of patients stopped their first regimen within a year due to side-effects, compared to 5% who stopped due to viral rebound and 7% who stopped due to difficulties with adherence. Women were almost twice as likely to stop their first regimen due to intolerance when compared to men (Monforte 2000).

Similarly, a study of 556 patients at the Royal Free Hospital found that 44% of patients had modified their first antiretroviral therapy regimen after a median of 14.4 months on treatment. Less than one third of those had modified their treatment due to virological failure; the overwhelming reason for changing treatment was due to poor adherence or toxicity (Mocroft 2001).

If you are considering changing your regimen due to the side-effects you are experiencing, be aware that the new regimen may not be as effective as the previous regimen, and that viral rebound may occur. It is also possible that the new regimen will bring its own unwanted effects.

Advice contained in the section Anti-HIV therapy: Choosing a combination may be relevant if you are concerned about side-effects.

Precautions when switching due to toxicity

The following issues need to be considered when choosing drugs to switch to:

• High levels of cholesterol, triglycerides and glucose intolerance: metabolic abnormalities such as hypercholesterolaemia and hypertriglyceridaemia may worsen, particularly after the introduction of a ritonavir-boosted protease inhibitor. The risk of further lipid elevations needs to be considered in the context of other risk factors for cardiovascular disease. Studies of switching to PI-sparing regimens have shown mixed results. See Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for further details.

• Peripheral neuropathy: a previous history of peripheral neuropathy, whether related to previous treatment, current treatment with isoniazid, dapsone, vincristine or D-drug nucleoside analogues (ddI, d4T, ddC), HIV infection, diabetes or alcohol abuse, is likely to affect the ability to use d4T, ddI or ddC in a new regimen since each drug is independently associated with peripheral neuropathy. The use of didanosine and d4T together has been shown to significantly increase the risk of PN compared with the use of either agent alone, and the risk was further increased when hydroxycarbamide was combined with either didanosine alone or didanosine and stavudine. See Neuropathy in Symptoms and illnesses: A to Z of illnesses for further details.

• Pancreatitis: a previous history of pancreatitis or elevated triglycerides may predispose to the development of pancreatitis in patients adding ddI to a new regimen, especially if accompanied by hydroxycarbamide. Female sex and a CD4 count below 200 cells/mm³ have also been identified as independent risk factors.

• Lactic acidosis: lactic acidosis has been associated predominantly with d4T treatment, and once lactate levels have returned to the normal range, NRTI-containing HAART has been successfully resumed if d4T is replaced with another NRTI . See Lactic acidosis / acidaemia in Symptoms and illnesses: A to Z of illnesses for further details.

• Hepatitis co-infection: hepatitis B or C co-infection has been demonstrated to increase the risk of hepatotoxicity and insulin resistance. Increased frequency of monitoring in patients with HCV or HBV is recommended, particularly in the case of agents known to be associated with hepatotoxicity (nevirapine, ritonavir). See Hepatitis C - key research in Symptoms and illnesses: A to Z of illnesses for further details.

• Diarrhoea: treatment modification due to diarrhoea requires attention to the risk of this side effect with protease inhibitors, especially nelfinavir, amprenavir, soft gel saquinavir and ritonavir-boosted protease inhibitors.

Switching due to body fat or metabolic changes

For further information on research into how switching antiretroviral therapy may affect metabolic abnormalities and body fat redistribution, see Treating body fat and metabolic changes - switching drugs in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

Treatment simplification

In the past few years various methods of HIV treatment simplification have been explored. The idea is that one uses a powerful HAART regimen as initial therapy to drive viral load down to undetectable levels, then moves to a less toxic and/or easier to take regimen, so that lipodystrophy and poor adherence can be minimised.

Approaches to simplification are discussed in Options for simplifying therapy in Anti-HIV therapy: Choosing a combination.

Changing for easier dosing

Another reason for some peoples change in therapy is to switch to an alternative formulation or dosing regimen (e.g. once daily dosing of all drugs). See Options for simplifying therapy in Anti-HIV therapy: Choosing a combination for further information.

Research into switching with undetectable viral load

A number of studies have provided encouraging evidence that people can maintain undetectable viral load when changing regimens. Nevertheless, a small proportion of people with undetectable viral loads do experience viral rebound after changing therapy. Viral load at the time of switch may be an influential factor; for example switching a PI for an NNRTI whilst viral load is suppressed below 500 copies rather than below 50 copies appears a risky strategy and several studies have reported a high proportion of virological failures in these circumstances.

Switch studies have looked at switching from PI-based therapy to nevirapine, efavirenz or abacavir. All of these studies looked at ways of simplifying treatment and reducing toxicity. Effects of treatment switches on lipid levels and body fat distribution are discussed in Treating body fat and metabolic changes - switching drugs in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

Evidence from studies which compared switching with maintenance of a PI-based regimen show that treatment failure, as measured by virologic rebound, is no more likely over 48 weeks of follow-up if treatment is switched. These studies are discussed under the relevant drugs in Drugs used by people with HIV (see Abacavir - overview, Efavirenz - overview or Nevirapine - overview.

It is difficult to make comparisons between studies of switching therapy, because the populations have differed. Important differences include:

• Prior NRTI exposure: the Trizal study included very few people with prior NRTI exposure, in contrast to the study conducted by Milos Opravil and colleagues in Switzerland and Italy, which showed a trend towards a higher virologic failure rate in patients who simplified to Trizivir.

• The NEFA study looked at switchers from PI-based therapy to a PI-sparing regimen, and had no continued therapy control arm

• The Trizal study of switching to abacavir-based triple NRTI therapy evaluated switching from either NNRTI or PI, but was not large enough (nor designed) to show whether a difference in outcome existed between those who switched from a protease inhibitor and those who switched from an NNRTI.

Research on switching due to toxicity

Dutch researchers found that between June 1996 and December 1999, 776 members of the 2470 person Dutch ATHENA treatment cohort, with a viral load below 500 copies m/L, had to change their antiretroviral therapy because of side-effects. The study sample had an average CD4 cell count of 365 cells/mm³, with 85% being men. The most commonly reported side-effects requiring a change in treatment were gastrointestinal (37%) and peripheral neuropathy (13%). Over a twelve-month period the Dutch research team found that 53% of the study group had to change their therapy again because of toxicity. Once again, gastrointestinal side effects (37%) and peripheral neuropathy (12%) were the main reasons for making yet another treatment change (Dieleman 2002).

Women appeared to be at a greater risk of having to make a second toxicity driven change, the authors speculating that this may be due to "sex dependent pharmacokinetics or adherence leading to higher plasma concentrations of the PI."

However, switching from a PI to the non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine appeared to be protective against a subsequent switch for toxicity reasons with a fivefold lower risk of subsequent side-effect related treatment changes. Of particular note was the low incidence of further treatment changes because of gastrointestinal problems in people switching to nevirapine: 22 people out of 100 were given nevirapine after complaining of gastric problems on their first PI based regimen and of these only one had to make a subsequent treatment change because of the recurrence or continuation of toxicity. There was no data on the benefits of switching to efavirenz as it was not licensed in the Netherlands during the study period.

However, it appeared that switching NRTIs as well as changing to nevirapine did not lessen the chances of experiencing side effects severe enough to warrant another treatment change. The researchers speculate that this may be due to the additional toxicity of the newly introduced NRTIs. Changing NRTIs at the same time as PIs did not reduce the risk of people having made subsequent toxicity-driven switches.

References

Dieleman JP et al. Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA Cohort. AIDS 16: 737-745, 2002.

Hayden R et al. Evaluation of side effect tolerability and quality of life (QOL) measures in patients after substitution of their PI/NNRTI with lopinavir/ritonavir (LPV/r). Antivir Ther 8: S392, 2003.

Hupfer M et al. Pilot study: ritonavir boosted indinavir treatment as a simplified maintenance monotherapy for HIV infection. Antivir Ther 8: S344, 2003.

Mocroft A et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS 15: 185-194, 2001.

Monforte AA et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. AIDS 14: 499-507, 2000.

Raffi F et al. Substitution of a nonnucleoside reverse transcriptase inhibitor for a protease inhibitor in the treatment of patients with undetectable plasma human immunodeficiency virus type 1 RNA. Clin Infect Dis 31: 1274-1278, 2000.

Smith CJ et al. Antiretroviral use and reasons for stopping amongst those on first-line HAART regimens Antivir Ther 8: S392, 2003.