Two-class ART just as good as three-class in the long-term, and has fewer side-effects

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Starting HIV therapy with drugs from the three main classes of antiretrovirals is not clinically or immunologically superior in the longer term to the more usual strategy of starting HIV treatment with drugs from two of the major antiretroviral classes, according the results of CPCRA 058 study, presented to the Sixteenth International AIDS Conference in Toronto on August 15th.

Not only was there no added benefit from initiating triple-class therapy, the investigators established that patients who did so were significantly more likely to experience side-effects than patients treated with a more conservative two-class antiretroviral combination. The study also compared the efficacy of initial two class combinations based on either protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs), and found that there was no difference between these combinations regarding the risk of an adverse immunological or clinical outcome, but that patients taking NNRTI-based therapy had a superior virological outcome in the short term.

There are limited data on the long-term consequences of starting antiretroviral therapy based upon a protease inhibitor, NNRTI or both. Therefore, between 1999 and 2002 investigators in the United States conducted a prospective study including 1397 patients starting HIV treatment for the first time to see if there were any significant differences in the risk of a new AIDS-defining illness, a fall in CD4 cell count below 200 cells/mm3, death or virological failure between patients starting therapy based on a protease inhibitor, or an NNRTI, or both a protease inhibitor and an NNRTI. Patients in the two triple combination arms also took two nucleoside reverse transcriptase inhibitors (NRTIs) while patients in the triple class arm took one nucleoside analogue.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

primary endpoint

The main result that is measured at the end of a clinical study to see if a given treatment worked (e.g., proportion of participants with viral suppression). The choice of primary endpoint is decided before the study begins.

The primary endpoint in this study was either illness, death or a CD4 count below 200 cells/mm3, while viral load responses were analysed as a secondary outcome.

At baseline, the patients had a median age of 38 years, 79% were men, 54% were black, 17% were Latino and median CD4 cell count was 163 cells/mm3. The median duration of follow-up was five years, and during this period 188 individuals died, and 388 developed a new AIDS-defining illness or experienced a fall in their CD4 cell count to below 200 cells/mm3.

Four hundred and seventy patients were randomised to the protease inhibitor arm, of whom 61% started treatment with nelfinavir, 39% with a ritonavir-boosted protease inhibitor. Four hundred and sixty-three were randomised to the NNRTI arm, 63% starting treatment with efavirenz. Approximately 55% in each of these arms took AZT/3TC Combivir as their nucleoside analogue backbone, with no other specific nucleoside backbone taken by more than 10% of patients.

After five years of antiretroviral therapy, patients treated with a protease inhibitor or an NNRTI were equally likely to progress to AIDS or death, but patients taking an NNRTI were 33% less likely to experience virological failure.

Attention was then turned to the efficacy of two-class and three-class combinations. After 32 months, patients taking two-class therapy and three-class treatment had comparable increases in their CD4 cell count (227 cells/mm3 versus 234 cells/mm3) respectively. The risk of death or AIDS was also comparable for two-class and three-class therapy, as was the risk of experiencing a fall in CD4 cell count to below 200 cells/mm3. The investigators also found that it did not matter if a person started treatment with a CD4 cell count below 200 cells/mm3 - initiating therapy with a three-class combination still did not confer any benefits.

However, the study revealed that patients taking three-class treatment were 58% more likely to discontinue treatment because of toxicities than those taking more conventional two-class therapy (p

“”NNRTI-based and protease inhibitor-based strategies for initial therapy do not differ for a composite outcome based on CD4 cell count decline, AIDS events, and death”, conclude the investigators. However, they add, “the NNRTI strategy was superior virologically to the protease inhibitor strategy.” They also draw attention to the increased rate of treatment discontinuations seen in the three-class arm, noting that this strategy is associated with “more drug toxicity.”

References

Mac Arthur RD et al. Long-term clinical and immunological outcomes similar in HIV-infected persons randomized to NNRTI vs PI vs NNRTI +PI-based antiretroviral regimens as initial therapy: results of the CPCRA 058 first study. Sixteenth International AIDS Conference, Toronto, abstract TuAb0102, 2006.