Second-line HIV therapy effective and durable in South Africa, and adherence support could improve rates of viral suppression

Second-line antiretroviral therapy in South Africa achieves durable viral suppression in three-quarters of patients and is associated with an increase in CD4 cell count, investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes. Therapy was based on a boosted protease inhibitor (lopinavir/ritonavir, Kaletra).

Unsurprisingly, adherence was associated with virological outcomes, with each 10% improvement in the rate of adherence more than doubling the chances of achieving an undetectable viral load.

An increasing proportion of people who have started HIV therapy in resource-limited settings have experienced first-line treatment failure. Second-line options are limited, and are usually based on a ritonavir-boosted protease inhibitor, which is taken in combination with two drugs in the NRTI class.

There is currently little information on the virological efficacy and durability of second-line treatment in poorer countries. However, it is important that this is established, and that an understanding is achieved of the factors associated with the effectiveness of such treatment.

“An improved understanding of second-line ART [antiretroviral therapy] in resource-limited settings will be critical in maximizing the durability of second-line regimens, preventing disease progression and reducing long-term AIDS-related mortality in high HIV-prevalence countries without access to third-line ART regimens,” explain the authors.

They therefore designed a study monitoring the outcomes of 136 patients who initiated second-line therapy in Durban, South Africa. This treatment consisted of lopinavir/ritonavir, which was taken in combination with two NRTIs (usually AZT and enteric-coated ddI). The investigators also conducted analyses to see which factors were associated with the efficacy of this treatment.

All the patients had experience of first-line therapy (usually efavirenz [Sustiva, Stocrin] with d4T and 3TC).

The median duration of first-line treatment was 13 months. At the time therapy was changed, the patients had a median CD4 cell count of 153 cells/mm³ and a median viral load of approximately 28,500 copies/ml.

Adherence in the six months before this therapy was discontinued had been poor. The median rate (calculated by pharmacy refill) was just 67%. The investigators believe that this low rate may have been partly due to the toxic effects of d4T, a drug which is no longer used in routine HIV therapy.

Switching to second-line treatment was associated with a significant improvement in adherence. In the first six months after the treatment change, the median rate of adherence was 100%. Adherence remained high throughout follow-up; the median rate at month 12 being 92%, which increased to 96% at month 24.

Almost three-quarters of patients (74%) had an undetectable viral load (below 50 copies/ml) six months after switching treatment. This rate of suppression changed little during the two years of the study.

Factors associated with viral suppression after twelve months of therapy were evaluated by the investigators. A higher rate of adherence was independently associated with an increased chance of an undetectable viral load at this time point. Each 10% increase in adherence more then doubled the chances of virological suppression (OR = 2.5; 95% CI, 1.3-4.8, p = 0.01).

Time to virological suppression was most rapid in patients who took 90% or more of their doses (p = 0.01).

Adherence of this level was associated with rates of virological suppression at months 6, 12, 18 and 24 of 73, 87, 93 and 97% respectively. In contrast, the rates of suppression at these time points for patients who took fewer than 80% of their doses were just 20, 44, 67 and 83% respectively.

Changing to second-line therapy also had immunological benefits. Median CD4 cell count increased to 228 cells/mm³ six months after switching therapy and continued to increase during follow-up, reaching a median of 330 cells/mm³ at month 24.

“The switch to second-line ART in South Africa was associated with an improvement in adherence and a rapid immunological recovery,” comment the authors.

However, they express concern that approximately one quarter of patients continued to have a detectable viral load. “Median adherence was not uniformly > 90% after initiation of second-line ART and differences in second-line adherence help explain why some patients… achieved virologic suppression after switch and other patients did not.”

They therefore conclude: “Novel adherence interventions may usefully target patients with second-line ART failure who – given a low likelihood of failure with major protease inhibitor resistance mutations – have a high likelihood of achieving viral suppression.”

Murphy RA et al. Second-line antiretroviral therapy: long-term outcomes in South Africa.  J Acquir Immune Defic Syndr, online edition. DOI: 10.1097/QAI.0b013e3182615ad1, 2012.