Many researchers now agree that resistance is the key reason why many anti-HIV drug regimens have only limited or short-term effects. Whenever HIV is still able to reproduce in the body of someone who is taking anti-HIV drugs, the selection process means that it is extremely likely that resistant strains will eventually emerge. Combination therapy tends to delay the onset of resistance, because new viruses that are resistant to the effects of one of the drugs may still be controlled by the other drugs.

After six years of treatment 38% of people experience viral rebound, according to a review of 4306 HIV-positive people attending six British HIV clinics (Phillips 2004; UK Collaborative Group on HIV Resistance 2005). The risk of a major mutation over this time period was 27%, while 20% of people developed resistance to at least two of the three main drug classes. An important finding of this study was that ritonavir (Norvir)-boosted protease inhibitor (PI)-based regimens are associated with a significantly lower risk of resistance mutations when compared to non-nucleoside (NNRTI)-based regimens.

An American study which followed nearly 1200 people commencing antiretroviral therapy for two and a half years also found that commencing treatment with an NNRTI was associated with a greater risk of drug resistance (Harrigan 2005).

However, NNRTI-based combinations have a lower risk of resistance compared to single PI therapy after controlling for factors such as baseline viral load and adherence (Bangberg 2005).

Maximal suppression necessary

From this perspective, any anti-HIV drug regimen is likely to fail if it only partially suppresses viral replication, which may be because the drugs are too weak or because the individual does not take the full dose regularly. However, the closer a drug regimen gets to suppressing HIV replication completely, the fewer new viruses with random, possibly resistance-conferring variations will be produced. This means that the emergence of drug resistance may theoretically be avoided for as long as the drugs continue to suppress viral replication. If in turn viral replication remains suppressed for as long as resistance is avoided, it is conceivable that once complete suppression of replication has been achieved, it may be maintained indefinitely.

Several triple-drug combination therapy studies have provided evidence to support this theory. For example, the development of nevirapine (Viramune) was almost abandoned a few years ago because treated people developed HIV strains that were highly resistant to nevirapine within weeks of starting treatment. However, in a trial in which nevirapine was combined with AZT (zidovudine, Retrovir) and ddI (didanosine, Videx / VidexEC), the combined effects of the drugs produced such a strong anti-HIV effect that 70% of recipients had viral loads below 200 copies/ml during treatment. In these people no nevirapine-resistant strains developed despite over a year of exposure to the drug, suggesting that controlling replication can indeed delay resistance. By contrast, resistance did develop in the majority of people who only took nevirapine plus AZT.

Likewise, people taking 3TC (lamivudine, Epivir) tend to develop 3TC-resistant strains within weeks if any measurable viral replication is taking place. But in people who achieved and maintained viral load below the level of detection during treatment with triple combinations containing 3TC, no 3TC-resistant strains were detected.

Early optimism about PIs was also clouded by the rapid emergence of resistant strains in trials in which people received the drugs on their own, or at doses now known to be too low. But in more recent studies in which PIs were given as part of triple combinations, the development of resistance was much reduced.

Resistance despite viral suppression?

Despite this optimism, there is some evidence that resistance can emerge slowly in people with undetectable viral load. Studies into long-term suppression of HIV due to antiretroviral therapy have found evidence of viral replication and mutation (Furtado 1999; Zhang 1999). It is now believed that antiretroviral therapy cannot eradicate HIV from the body completely, and that HIV continues to reproduce at low levels despite treatment. This raises the prospect of resistance emerging even among people with very low levels of HIV in their blood. This may, in turn, lead to treatment failure and viral rebound.

A Swedish group confirmed that resistance mutations do emerge among people with viral loads between 50 and 500 copies/ml (Soderborg 1999).

However, an analysis of data from the Frankfurt HIV Clinic Cohort offers a more optimistic scenario. Four hundred and six drug-naive people began a three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a PI or NNRTI. Despite a relatively high average baseline viral load of 250,000 copies/ml, 91% had achieved viral load below 500 copies/ml by week 24 of treatment. Twenty per cent of these experienced viral rebound over two years of follow-up. However, the likelihood of rebound fell over time. In people who maintained viral load below 500 copies/ml for at least one year, the rate was calculated to be one rebound in every 12.4 person-years. The authors concluded that so long as complete adherence can be maintained over the long-term, today's drug regimens appear able to suppress viral replication for more than ten years (Phillips 1999).

More recent data have also urged optimism. A study of 98 HIV-positive patients with detectable viral loads despite being on antiretroviral therapy indicated that the development of new resistance mutations occurred relatively slowly, at an average rate of 1.61 mutations per person per year. The development of resistance was linked to higher viral loads, a faster viral load increase and having fewer pre-existing resistance mutations (Napravnik 2005).

Starting early?

Some researchers have argued that the new virological data also give support to the theory that the earlier treatment is started, the more effective it is likely to be. Recently-infected people will have undergone fewer generations of viral replication, so are less likely already to harbour HIV strains that will be resistant to drug treatment.

However, mathematical models have calculated that daily virus production in a chronically infected individual produces every mutation one thousand times a day in the absence of any pressure from a particular drug. In other words, there is no 'best time' to intervene, since the selective pressure of a drug on the virus population 'starts the clock' on drug resistance. In newly-infected people, however, virus turnover and the mutation rate is ten times higher, implying that drug resistance will emerge more quickly in the newly infected than in those who have been infected for a number of years.

Always change at least two drugs

There are also implications for people who experience disease progression or worrying laboratory tests such as falling CD4 cell count or rising viral load while taking anti-HIV drugs. It is now clear that adding or changing a single new drug in a failing regimen is likely to select for drug resistance, because the impact of that one new drug will be insufficient to block viral replication.

Experts now advise that any treatment change should always consist of at least two new drugs. Those drugs should be chosen to minimise the risk that the HIV in the body will already be cross-resistant. This view was first endorsed in treatment guidelines published in the United Kingdom and the United States in 1997.

See Anti-HIV therapy: Changing treatment for further discussion of this issue.

Interrupting treatment?

Taking a short break from treatment, may mean some resistance mutations 'disappear'. The risks and benefits of interrupting treatment to minimise resistance are discussed in Anti-HIV therapy: Structured treatment interruption.

Adherence

The reason why doctors place so much stress on the importance of sticking rigidly to the suggested dose and regularity when taking anti-HIV drugs is that missing or reducing doses could allow drug levels in the blood to fall to sub-optimal levels. This will allow viral replication to occur and thus greatly increasing the risk of the emergence of resistance.

Taking a combination as prescribed at least 95% of the time is associated with a significantly lower risk of resistance compared to adhering to therapy 80 to 90% of the time (Harrigan 2005). While virus can be suppressed when adherence to NNRTI therapy is moderate, adherence over 95% increases a persons chance of suppressing HIV when taking an NNRTI (Bangsbery 2005).

See What level of adherence is necessary? in Anti-HIV therapy: Adherence for further information, and Practical strategies for adherence in Anti-HIV therapy: Adherence for discussion of practical ways of maintaining good adherence to treatment.

Injecting drug use

A large Canadian study comparing rates of resistance in antiretroviral-naive individuals with and without a history of injecting drug use (IDU) has concluded that there are no major significant differences between rates of resistance of the two groups during the first two-and-a-half years of treatment. However, the IDU rate of NNRTI resistance development was slightly elevated, although this was of borderline significance (Wood 2005).

Previous research into 15 injecting drug users followed for four years after seroconversion, suggested the drug users experience a higher rate of viral turnover and thus are at greater risk of drug resistance (Carneiro 1999).

For discussion of injecting drug use and disease progression, see the entries Factors affecting disease progression and Non-infectious co-factors in The immune system and HIV: How HIV damages the immune system.

References

Balfour V et al. Adherence to HIV protease inhibitor therapy and maximal suppression of plasma viremia: when is adherence enough? AIDS Impact, Fourth International Conference on the Biopsychosocial Aspects of HIV Infection, Ottawa, 1999.

Bangsberg D et al. 95% Adherence is not necessary for viral suppression to less than 400 copies/mL in the majority of individuals on NNRTI regimens. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 616, 2005.

Carneiro M et al. The effect of drug-injection behaviour on genetic evolution of HIV-1. J Infect Dis 180: 1025-1032, 1999.

Harrigan PR et al. Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. J Infect Dis 191: 339-347, 2005.

Napravnik S et al. HIV-1 drug resistance evolution among patients on potent combination antiretroviral therapy with detectable viremia. J Acquir Immune Defic Syndr 40: 34-40, 2005.

Paterson DL et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 133: 21-30, 2000.

Phillips AN et al. Low and decreasing rate of viral rebound with prolonged viral suppression on HAART: insights into long-term impact of resistance. Antivir Ther 4: 120, 1999.

Phillips AN et al. Risk of development of drug resistance in patients starting antiretroviral therapy with three or more drugs in routine clinical practice. Antivir Ther 9: S151, 2004.

Soderborg K et al. Detection of drug resistance mutations in HIV-1 patients with early viral rebound during an on-going combination therapy programme. Antivir Ther 4: S80, 1999.

UK Collaborative Group on HIV Drug Resistance. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS 19: 487-494, 2005.

Wood E et al. Rates of antiretroviral resistance among HIV-infected patients with and without a history of injection drug use. AIDS 19: 1189-1195, 2005.