Most patients on incompletely suppressive therapy maintain CD4 counts and stable viral loads

Two-thirds of patients on anti-HIV therapy that failed to reduce their viral loads to undetectable levels (‘incompletely suppressive therapy’ or ISR) maintained or increased their CD4 counts for over two years, a study from the University of Michigan has found. Viral loads remained stable in an even larger proportion – 80% – of patients. The study is published in the October 15^th edition of Clinical Infectious Diseases.

However, 63% of patients developed a new resistance mutation while on ISR, and 84% of those on a protease inhibitor-based therapy developed increased resistance, of varying degrees, to protease inhibitors (PIs).

The study supports the findings of previous studies that immune function and virological control can be maintained for a considerable time if the patient is kept on their ostensibly ‘failing’ therapy. The present study, however, had a longer average follow-up period (two and a quarter years) and maximum follow-up period (four years).

Study population

The researchers took 47 patients who had persistent viral loads despite being on potent antiretroviral therapy. Most patients had a ‘genotype sensitivity score’ to their current regime of zero, in other words their patterns of resistance mutations indicated that they were sensitive to no drug in their current regimen. Their median baseline viral load was about 20,000 copies/ml, their median baseline CD4cell count was 277 cells/mm³ (interquartile range, 157-424 cells/mm³) and their median CD4 nadir (lowest-ever CD4 count) was 105 cells/mm³ (IQR 27-178).

The vast majority were men and in 70% the risk factor for HIV was male-male sex. Their average time on potent antiretroviral therapy was seven and a half years, during which they had taken an average of four NRTIs, one NNRTI and three protease inhibitors.

They had an average of five resistance mutations to NRTIs and all but two had thymidine analogue mutations, which reduce sensitivity to AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit) and most of the other NRTIs. One of the patients that did not have TAMS had the multi-NRTI mutation Q151M. Eighty-five per cent of patients had the M184V/I mutation to 3TC/FTC. They averaged one mutation to the NNRTIs; 36% had two or more. And they averaged six mutations to the PIs, with 34% having over two of the so-called primary mutations which confer high-level resistance.

Seventy-two per cent were maintained on a regimen containing a PI, and 36% on an NNRTI: this adds up to more than 100% because some were on both classes. Three patients (6%) were on triple NRTIs.

Results

Immunologic failure was defined as a greater than 25% decline in CD4 count that persisted for more than three months, and virologic failure as an at least threefold rise in viral load (≥0.5 log₁₀/copies/ml), also persisting for more than three months.

Twenty per cent of patient had experienced immunologic failure by the end of the first year and 35% by the end of year two, and by the end of year four 43% had failed immunologically. No further immunologic failures took place after two-and-a-half years, though less than a quarter of patients were followed up for all four years; this was largely because as new drugs (tipranavir, Aptivus) and T-20 (enfuvirtide, Fuzeon) came along, patients were allowed to take them but excluded from further participation in the study.

Virologic failure as defined in the study was less common. By the end of year one 10% had failed, by year two 16% and by year four 22%, though again no further virologic failures occurred after 2.5 years.

Certain types of patients were more likely to fail. Patients with a nadir CD4 count of under 100 cells/mm³ were over five times as likely to fail virologically and over twice as likely to fail immunologically than other patients. Patients with a baseline viral load of over 100,000 copies/ml (19 patients) were nearly five times as likely to fail immunologically: none of these patients, however, failed virologically.

Patients with the M184 mutation who were kept on 3TC (lamivudine, Epivir) or FTC (emtricitabine, Emtriva) were over twice as likely to fail virologically; however they were only half as likely to fail immunologically, possibly the researchers speculate, because the 184 mutation re-sensitised patients to their other NRTIs. None of these relative risks achieved statistical significance because of the small size of the study, so could have been due to chance, though the association with low CD4 nadir was strong.

Twenty-seven out of 47 patients had resistance tests while receiving the incompletely suppressive regimen, of which 70% (19) were on a regime containing a PI, 40% (11) on an NNRTI and two on a triple-NRTI regimen. Seventeen patients (63%) developed a major resistance mutation to at least one class of antiretrovirals during the follow-up period; the average number of mutations developed was two. Eighty-four per cent of patients who were taking PIs developed at least one new PI resistance mutation, with the average number being three, and 53% developed a new primary mutation; this could potentially compromise future PI therapy. Forty-five per cent of those who were taking NNRTIs developed one new NNRTI mutation (none more than one); and nearly half of the patients developed new thymidine analogue mutations.

Conclusions

The researchers comment: “Our study shows that many patients with highly drug-resistant HIV infection for whom an optimised regimen is unavailable can have sustained immunologic and virologic responses to an ISR.”

They say that their findings remain relevant, despite the arrival of new resistance-beating drugs such as the PI darunavir and the NNRTI etravirine, and new classes of drugs such as the integrase, maturation and CCR5 inhibitors.

In order to avoid the accumulation of protease inhibitor mutations, which could compromise future PI sensitivity, they suggest “a potential role for a simplified, PI-sparing ISR in order to prevent additional mutations to the protease class.”

“Despite the availability of new agents today,” they write, “some patients with highly drug-resistant HIV infection may continue to have no viable treatment option other than to continue to receive an incompletely suppressive regimen for a prolonged period of time.”