An increasing problem - especially in the UK

There have been a growing number of reports of the transmission of drug–resistant strains of HIV. A rising proportion of newly-infected people are being infected with strains of HIV that are resistant to AZT and/or other agents.

In the UK, the proportion of people becoming infected with HIV resistant to t least one drug increased from 13% in 1996-1997 to 25% in 2002 (see chart below).

Resistance to nucleoside drugs increased from 9% to 17%, to protease inhibitors from 4% to 9%, and to non-nucleoside (NNRTI) drugs from 1% to 7% (and to 10% in 2003, though this figure was based on a small number of samples).

One quite troubling fact is that transmitted drug resistance appears to be more common in the UK than it is in the rest of Europe (Wensing). The evidence we have from other EU countries suggests that only about 10% of transmitted HIV has resistance to at least one drug, and 13.5% of those who caught HIV since 2002. It is not at all clear why the UK has higher rates of transmitted resistant virus. It cannot be due to the UK’s exceptionally high number of people from sub-Saharan Africa as there was less resistance seen in non-B subtypes of HIV (i.e. those more commonly seen in the developing world). Whereas 25% of all newly-diagnosed people had resistant HIV in 2002, among gay men the proportion was 27%. It may therefore be something to do with the fact that the UK, as far as we can tell, now has the highest incidence of new infections among gay men of any country in Europe (see Epidemiology for more on this).

(Source: An update on HIV drug resistance in the United Kingdom – CDR Weekly, 25.11.04 – available at http://www.hpa.org.uk/cdr/archives/2004/cdr4804.pdf)

Firstly, it is important not to confuse the proportion of people who catch drug-resistant HIV and the proportion of people on treatment who have it. In the latter case, three-quarters of all patients (74%) had resistance to at least one drug in 2002/3, 46% to more than one class of drug, and 10% to at least one drug in all three major drug classes.

However HIV with drug-resistance mutations often has impaired replicative capacity compared to non-resistant ‘wild type’ virus and for this reason is less often transmitted, both because for this reason it tends to form a minority of differing viral strains within the source patient and because it finds it less easy to establish a new infection (is less virulent).

When it is transmitted, however, the entire viral population in the recipient is drug-resistant, which means they are essentially resistant for life.

It is also important to note that the acquisition of drug resistant virus does not mean clinical failure. Twenty per cent of NRTI resistance is due to the single M184V mutation that confers resistance to 3TC or its near-identical cousin, FTC (UK Collaborative Group on HIV Drug Resistance). Patients with resistance to 3TC or FTC are often kept on the drug because HIV with the M184V 3TC resistance mutation has impaired replicative capacity. Catching 3TC/FTC resistant virus still allows the use of all other NRTIs.

More troubling are high levels of resistance to the thymidine analogue drugs AZT and d4T (which may also compromise response to abacavir). In one study of treatment- experienced patients, 48% of patients had these mutations. Much of this resistance is due to HIV being acquired from long-term survivors who may have acquired it through being given AZT monotherapy or NRTI dual therapy in the pre-HAART era.

The increase in non-nucleoside (NNRTI) resistance is, unfortunately, probably inevitable at present. NRTI + NNRTI HAART regimens have become the preferred first choice for patients in the UK and the NNRTI drugs efavirenz and nevirapine, like 3TC, have a low resistance threshold. Until new-generation NNRTIs that have a higher resistance threshold come along, NNRTIs are essentially ‘one shot’ drugs that cannot be used after one treatment failure on them.

However second-line therapies based on protease inhibitors (PI) are in general much less susceptible to the generation of resistance. Furthermore PI resistance is an accumulating rather than all-or-nothing phenomenon; most patients with 1-3 PI resistance mutations will respond to modern boosted PIs such as lopinavir/ritonavir (Kaletra).

The incidence of transmission of HIV resistant to more than one drug class, although it has increased in recent years, remains quite low (see chart below). Only 4.6% of patients acquiring HIV in 2002/3 acquired HIV resistant to two or more classes of drug, and only two per cent to three classes.

However once patients acquire HIV with this degree of resistance, their treatment choices will almost certainly be compromised.

Reference

CDR weekly. An update on HIV drug resistance in the United Kingdom. Vol 14 (48), 25 November 2004.

UK Collaborative Group on HIV Drug Resistance. Estimating HIV-1 drug resistance in antiretroviral-treated individuals in the United Kingdom. J Infect Dis 192: 967-973, 2005.

Wensing AMJ et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: Implications for clinical management. J Infect Dis 192: 958-966, 2005