First-line treatment for HIV-2: superior outcomes seen with a boosted protease inhibitor

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An antiretroviral combination based on a boosted protease inhibitor should be “considered as first-line ART for patients with HIV-2 infection", an international team of investigators recommend in the May 15th edition of Clinical Infectious Diseases.

After twelve months of treatment, superior virological and immunological outcomes were seen in patients taking a combination of drugs that included a boosted protease inhibitor, compared to people treated with the recommended triple nucleoside reverse transcriptase inhibitor (NRTI) regimen.

“We showed better viral suppression and higher CD4 cell recovery associated with PI/r [protease inhibitor/ritonavir] than with a triple NRTI regimen,” write the investigators.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

first-line therapy

The regimen used when starting treatment for the first time.

detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.

HIV-2 is found predominantly in western Africa; a small number of cases are diagnosed in Europe and North America each year.

HIV-2 infection is associated with slower disease progression, but its natural resistance profile means that fewer drugs are available for its treatment than HIV-1. In particular, drugs from the non-nucleoside reverse transcriptase inhibitor (NNRTI) class cannot be used.

Guidelines issued by the World Health Organization (WHO) in 2010 recommended that patients with HIV-2 should start antiretroviral therapy with a triple NRTI regimen. Protease inhibitor-based therapy is reserved for second-line treatment.

No randomised controlled trials have assessed the efficacy of specific combinations in patients with HIV-2. Nevertheless, some small observational studies have shown superior outcomes in patients treated with a ritonavir-boosted protease inhibitor.

Investigators from Europe, Gambia and North America therefore conducted an observational study to compare the effectiveness of triple NRTI and boosted-protease inhibitor regimens in HIV-2-infected people who started first-line treatment between 1998 and 2008.

A total of 170 patients were included in their analysis, 126 of whom (74%) received a boosted protease inhibitor.

The most commonly used triple NRTI regimen (72%) was 3TC, abacavir and AZT, and 61% of patients treated with a boosted protease inhibitor received lopinavir/ritonavir.  

Changes in viral load and CD4 cell count were compared between the two regimens after three and twelve months of treatment.

Information was also gathered on the proportion of patients achieving “treatment success” after twelve months – defined as an undetectable viral load and an increase in CD4 cell count of at least 50 cells/mm3.

Viral load changes were comparable between the two combinations for the first three months of therapy. Thereafter, viral load remained low in patients who received a boosted protease inhibitor, but increased in patients treated with three NRTIs. After a year of treatment, patients taking a triple NRTI regimen had a higher viral load than those receiving a boosted protease inhibitor (4.0 vs 2.2 log10 copies/ml; p = 0.005).

Analysis was then restricted to the subset of patients who had an undetectable viral load at the start of therapy. This showed that 8% of patients taking the triple NRTI regimen, compared to 3% of people taking a boosted protease inhibitor, had a detectable viral load at least once within the first twelve months of treatment.

Investigators turned their attention to immunological responses.

As with viral load, these were comparable during the first three months of therapy.

However, by month twelve, patients taking a ritonavir-boosted protease inhibitor had an average increase in their CD4 cell count of 76 cells/mm3 compared to baseline, whereas individuals receiving three NRTIs had had an average fall of 60 cells/mm3 compared to baseline (p = 0.002).

This meant that CD4 cell counts at month twelve were significantly higher among patients taking a protease inhibitor (327 vs 191 cells/mm3; p = 0.001).

Restricting analysis to patients with a baseline CD4 cell count above 200 cells/mm3 showed similar results. After twelve months, patients taking a boosted protease inhibitor had an average CD4 cell count increase of 52 cells/mm3, compared to a fall of 99 cells/mm3 among people taking three NRTIs (p = 0.02). A similar trend was also present for patients with a baseline CD4 cell count below 200 cells/mm3.

A sensitivity analysis that involved the 75% of patients taking currently recommended regimens showed superior virological and immunological outcomes among the people receiving a boosted protease inhibitor.

The investigators then assessed the proportion of patients who had a successful response to treatment. They found that 55% of patients taking a boosted protease inhibitor had this outcome, compared to just 10% of individuals treated with three NRTIs (difference, p = 0.003).

HIV-2’s natural pattern of resistance could explain the poorer responses seen in patients treated with three NRTIs, the investigators suggest.

None of the patients died, and the proportion developing a new AIDS-defining illness was low and did not differ significantly between the regimens.

“A combined end point reflecting successful clinical, therapeutic, virological and immunological measurements at month 12 showed superiority of PI/r over triple NRTI regimens,” comment the investigators.

They call for “further research… to evaluate the optimal cART regimen for treatment-naïve patients with earlier HIV-2-infection, at best through a randomized controlled trial”.

References

Benard A et al. Immunovirological response to triple nucleotide reverse-transcriptase inhibitors and ritonavir-boosted protease inhibitors in treatment-naïve HIV-2-infected patients: the ACHIEV2E collaboration study group. Clin Infect Dis 52: 1257-66, 2011 (click here for the free abstract).