Clinical and immunological benefits lasting at least three years reported by large Kenyan antiretroviral programme

Background

Despite a number of studies showing that ART can be effective in resource-limited settings, there remain concerns about treatment adherence and how long the drugs will remain effective (including the potential for the emergence of resistance) — especially when treatment programmes have no or little access to viral load and resistance testing.

Many initiatives have sprung up using different models to provide ART in such settings. In 2001, Moi University and Moi Hospital formed a collaborative partnership with Indiana University and launched the Academic Model for the Prevention and Treatment of HIV/AIDS (AMPATH) to improve the care and treatment of people affected by HIV/AIDS in western Kenya.

A large-scale antiretroviral treatment (ART) programme in Kenya achieves sustained clinical and immunological benefits for most treated patients according to a report in January’s issue of AIDS.

The retrospective study of over 2000 patients concluded that the median time to failure on the first-line regimen in Kenya may be about three years. However, poorer responses were seen in patients who did not report perfect adherence, and the study could not factor in the results in almost a quarter of the programme’s patients who were lost to follow-up.

Nonetheless, the study’s investigators conclude that "the findings document the viability and effectiveness of large-scale HIV treatment initiatives."

The AMPATH programme

AMPATH provides comprehensive HIV care services at Moi Hospital, one district hospital and six rural health clinics. The programme uses algorithms consistent with World Health Organization (WHO) guidelines to determine which patients should be put on ART (symptoms of advanced disease or CD4 cell counts below 200 copies/mm³). However, for the first two and a half years, funding limited how many patients could be put on treatment, so clinicians prioritised those who were most severely ill (later the initiative received funding from the US President's Emergency Plan for AIDS Relief or PEPFAR).

AMPATH’s patients receive more frequent monitoring than in some other clinic-based treatment programmes, with a visit to the clinic two weeks after ART was started and monthly visits thereafter (sometimes extended to every two months for highly adherent patients). At each visit, patients underwent clinical and adherence assessments and received their monthly supply of drugs, which was usually nevirapine/d4T/3TC (except for people on TB treatment who were given efavirenz in place of nevirapine). Every six months, patients' CD4 cell counts and liver enzymes are monitored (although in the early part of the programme laboratory measurements could not always be performed because of financial constraints).

To determine how effective the AMPATH programme was, researchers performed a review of the programme’s prospectively collected data. Information on CD4 cell counts, weight, mortality, loss to follow-up and adherence were drawn from the records of 2059 people placed on ART between November 2001 and September 2004.

The programme uses a questionnaire to record the range of participant’s adherence to treatment (perfect, most, poor etc.) but only ‘perfect’ and ‘not perfect’ adherence were assessed in the study. Mortality data were collected using a passive surveillance system (in other words, patient’s lost to follow-up were not actively tracked down to see whether they were still living).

Study results

Follow-up: As of February 2005, the median duration of follow-up for programme participants was 40 weeks, which suggests that the vast majority were enrolled in 2004 — after the availability of PEPFAR funding. 505 people (24.5%) were lost to follow-up. This is an extremely high figure which suggests either a high rate of unrecorded deaths, unusual population mobility, or conversely, that people had trouble making the frequent trips to the clinic.

Loss to follow-up differed significantly between clinics, approaching 30% at first year in clinics 1 and 3, while the rates in clinics 2 and 4 were less than half of that rate (P

Mortality:

Death was documented in 111 patients (5.4%) but as noted a large number of those lost to follow-up were probably dead. This would suggest quite a high hidden mortality rate but this could simply be the result of the programme prioritising treatment of the most severely ill. The study noted that the risk of death for a patient with a CD4 cell count below 100 cells/mm³ when treatment began was over three times higher than that for a patient with CD4 cell count > 100 (P

CD4 cell response:

CD4 cell counts increased by 109 cells (mean) during the first six weeks on therapy and more slowly thereafter, resulting in overall CD4 cell count increases of 160, 225 and 297 cells at 12, 24, and 36 months respectively. Patients reporting perfect adherence had the best responses, with a mean increase of 170 cells at first year, compared to an increase of 123 cells among those who were not perfectly adherent (P

Adherence:

Data were available in 1766 people. 78% reported perfect adherence at every visit. This rate is somewhat lower than has been reported in other studies in resource limited settings (see http://www.aidsmap.com/en/news/78D3FC87-A5B0-443D-8AB7-6B646C1C29D7.asp and http://www.aidsmap.com/en/news/3E8B197B-3939-46E6-BF00-0CDE13F722D5.asp). The study says little about what sort of treatment preparedness training, if any, patients received.

Weight gains:

ART caused significant increases in weight which then tapered off. The average increase in weight over the three years was 4.42kg (P

Time to failure:

As already noted, viral load tests are too expensive for this programme, so the study defined treatment failure as a greater than 25% decrease in CD4 cell counts. Less than 50% of the patients on treatment after three years experienced treatment failure. It should be noted, however, that given the median follow-up, the number of patients may not be large. Patients who did not perfectly adhere to treatment had a shorter time until presumed antiretroviral therapy failure (P

Conclusion — programme a success but concerns for the future

Even though the results in this study aren’t perfect, the roll-out of ART had a dramatic and beneficial impact for many of the patients in this programme, and the data suggest that benefit may last for up to three years.

However, it is likely that virological failure probably precedes CD4 cell failure by several months, and during this period of time, resistance to treatment may become heightened which could reduce response to future regimens. Resistance may be more likely to be transmitted than if treatment were switched upon resistance testing or viral load data. Prevention work in this context becomes even more important to preserve the benefits of first-line therapy in this region.

Also, the investigators write "because of the cross resistance between the non-nucleoside reverse trancriptase inhibitors, second-line regimens will need to be protease inhibitor-based... [and] use of a protease inhibitor in the second-line regimen has significant cost and monitoring implications that must be addressed as HIV treatment programs are extended in the developing world."