A Canadian study has found that treatment failure due to drug resistance did not significantly contribute to the mortality of people with HIV in British Columbia between 1997 and 2001. The study, published in the July 15th edition of The Journal of Infectious Diseases (now available online), is the first to suggest that the exhaustion of treatment options due to drug resistance may not cause as much loss of life from HIV/AIDS as previously thought, and that it is insufficient and/or intermittent therapy that is more likely to lead to death.
Researchers from Vancouver’s British Columbia Centre for Excellence in HIV/AIDS analysed the post-HAART cause of death in all individuals who were enrolled in the province’s free-to-all Drug Treatment Programme between July 1997 and December 2001. The 637 deaths were then classified, and 83 (13%) accidental deaths were removed from the analysis. Of the remaining 554 deaths, 383 (69.1%) were directly related to HIV infection, 34 (6.1%) related to liver disease, 25 (4.5%) to various cardiac conditions, 20 (3.6%) to viral and/or bacterial infections, 18 (3.2%) to cancers, 43 (7.8%) to other causes, and 31 (5.6%) to unknown causes.
Of these 554, 58 (10.5%) had enrolled in the free drug programme but had not received any antiretroviral therapy before their deaths. Plasma samples were not available for genotyping for 99 (20%) of the 496 treated individuals. However, since the median time on treatment for this group was two months (IQR, 0-4 months), it is unlikely that drug resistance would have played a major role in their deaths.
Similarly, of the remaining 397 individuals for whom plasma samples were available, 147 (37%) died when their last viral load measurements had been below 500 copies/ml, suggesting that their antiretroviral therapy had not been compromised by major resistance mutations. The last plasma samples from another 65 individuals on HAART with viral loads above 500 copies/ml were also found not to have been harbouring any major resistance mutations.
Consequently a total of 167 (44.1%) individuals’ last plasma samples were found to have been harbouring viruses with major resistance mutations at the time of death, the majority of which (142) were resistant to one or more nucleoside analogues, primarily 3TC (101, 26.6%). Only 83 (21.9%) and 53 (13.9%) harboured resistant mutations to any NNRTI or protease inhibitor (PI), respectively. Resistance to drugs from two classes was found in 23.4% of all samples, but resistance to drugs from all three classes (which in 2001 would have meant broad-spectrum resistance to most nucleosides, all available NNRTIs, and all PIs other than amprenavir, which became available on expanded access in 1998, and Kaletra, which became available on expanded access in 2000) was found in only 5.8%.
Unsurprisingly, individuals who had started mono- or dual therapy were significantly more likely to harbour resistant HIV than those who had received HAART exclusively (p <.001 all="" begun="" classes.="" conferring="" drug="" fact="" haart="" had="" in="" mutations="" none="" of="" resistance="" their="" therapy="" those="" three="" to="" triple-drug="" who="" with="">
To put these data into perspective, the researchers compared their findings with results from all those enrolled in the drug programme during the same period who were alive but who had viral loads above 500 copies/ml.
Interestingly, they observed “a dramatically higher prevalence of antiretroviral resistance in the virologic failure group than in the mortality group.” Of the 1220 individuals in the virologic failure group, 924 (75.7%) harboured HIV with resistance to at least one drug class, compared to only 44.1% of those who died (p <.0001 also="" and="" classes="" compared="" died="" drug="" failure="" group="" higher="" in="" of="" or="" prevalence="" resistance="" respectively="" significantly="" similarly="" the="" those="" three="" to="" two="" virologic="" was="" who="">
This paradox – that drug resistance is common in individuals experiencing virologic failure but remaining alive, but uncommon in those who have died – strongly suggests that it is drug exposure that is the key factor affecting survival.
Those who died only received antiretroviral therapy for an average of 19 months, which, “given the large number of treatment possibilities today,” argue the authors, “is not long enough to have attempted and failed all possible therapy combinations.” This suggests that that those who died used antiretroviral therapy only intermittently and/or discontinued it prior to their deaths. In fact, the majority of those who died, including about 40% whose last viral loads on therapy were below 500 copies/ml, discontinued therapy a median of two months prior to their deaths, for unknown reasons.
Although recent reports find that drug resistance is becoming increasingly prevalent, concerns from some quarters that it will cause significantly increased illness and death in the era of boosted PIs and other new therapeutic options may well be overstated. However, new agents and new classes of drugs will need to be developed continually in order to keep one step ahead of HIV for those who have broad-spectrum resistance to currently available drugs.
The authors conclude that “this study strongly indicates that treatment failure due to antiretroviral resistance was not a major factor influencing mortality in this cohort... for most of the individuals studied, insufficient and/or intermittent exposure to antiretroviral agents, co-morbidities and other factors likely played a larger role.”
Further information on this website
Resistance - factsheet
Resistance - booklet in the Information series for HIV-positive people (pdf)
Infection with drug-resistant HIV has little effect on CD4 cell counts in the absence of therapy - news story
Resistant HIV strains persist after at least five years on suppressive HAART - news story
Recsky MA et al. Antiretroviral resistance among HIV-infected persons who have died in British Columbia, in the era of modern antiretroviral therapy. J Inf Dis 190, 2004 (published electronically).