CROI: MSF reports good responses on PI-based second-line ART regimens even though switch from failing regimens comes late

Background

Since 2001, MSF-supported programmes have successfully pioneered to the use of first-line ART in resource-limited settings across the world. However, based upon the experience in developed countries, one can assume that with increasing access to, and time on, ART, a growing number of people will fail their first-line regimens and require second-line treatment.

However, in resource-limited settings where there is no access to viral load monitoring, clinicians have to base the decision to switch upon signs of clinical progression in the patient or, in some cases, upon significant declines in CD4 cell count — which may only happen long after the first-line regimen has failed to suppress the virus. Ongoing replication could lead to resistance to all the drugs used in the first-line regimen. In addition, the lack of alternative antiretroviral drugs means that second-line ART regimens are often suboptimal.

The late switch and limited antiretroviral options in resource-limited settings could adversely affect the therapeutic outcomes on second-line ART — but so far, data on this have been limited.

Protease inhibitor- (PI) based antiretroviral regimens (ART) can still be effective as a second-line treatment in resource-limited settings (at least in the short run), even when the switch from first-line therapy comes quite late and when the backbone nucleoside analogue drugs used are sometimes recycled, according to two presentations from Médecins sans Frontières (MSF) on Monday at the Fourteenth Conference on Retroviruses and Opportunistic Infections held in Los Angeles. However, the second report showed extremely good responses when the protease inhibitor was Kaletra.

According to the presenters, even after years on first-line treatment, second-line regimens are not being used by a great number of MSF programme participants, but part of this was because second-line treatment is not easily accessible, and the fact that “we have no option in case of failure,” said Dr Alexandra Calmy who presented a paper on the global MSF experience.

Nevertheless, she noted that the numbers moving onto second line are steadily increasing. “We have to start asking about what we will use for 3rd line,” said her colleague Dr Laurent Ferradini, who presented data on Kaletra-based second-line treatment in Cambodia.

Results

Since 2001, only small numbers of patients have switched to second-line, but the numbers are cumulative. After one year, only 60, and by five years, only 352 had switched to second line, for a rate of 4.4 per 1,000 person years.

Looking just at those 352 patients, 57% were women; the median age of 35 years; the median CD4 cell count was 99 cells at switch (and the median nadir CD4 was 37); and viral load (in those for whom it was available) was 44,000 copies/ml.

The median duration of first-line therapy was 20 months before switching to second line and patients were followed up on second-line for a median of seven months.

The reasons for switching were a CD4 count below 50 cells in 32%; the occurrence of a WHO stage III or IV clinical event in 31%; a fall in CD4 cell counts to or below baseline values when they started their first-line regimen in 33%.

The second-line regimen included Kaletra in 46% of the patients and nelfinavir in 47% of the patients, while a small percentage began other therapies. 63% of the patients changed both of their nucleoside analogue backbone drugs, and 37% changed at least once, however, only 20% began treatment on the newer drug, tenofovir.

Kaplan Meier curves on the probability of survival showed that 91% of the patients who switched to second line where still alive at six months, and 86% were still alive at one year (patients lost to follow-up were considered dead). In multivariate analyses, having a CD4 cell count nadir below 50 cells at the time of switch was associated with an 86% increased in the risk of death (p=0.02). Of note, age, sex, WHO stage at start of first-line or second line regimen, or the choice of nucleoside analogues in their second-line regimen were not associated with death.

As of December 2006, 297 patients who began second-line were still alive; there had been 26 deaths; 18 patients were lost to follow-up after nine months; and six patients quit taking ART. The median gain in CD4 counts was 81 cells at six months and 131 cells at twelve months. 68% had an increase of at least 50 CD4 cells at six months.

Study to assess characteristics and outcomes of MSF patients on second-line regimens

So researchers including Dr Calmy working with MSF examined the data records for over 80,000 patients in 50 MSF-supported programmes in 22 countries in Africa, Asia, and Central America to see how many patients had been switched to second-line therapy, at what point was a switch made, how effective was the change to second- line therapy, and to investigate factors associated with death and or loss-to follow-up.

The larger question behind the study is how successful is ARV treatment in the absence of virological monitoring and in the absence of treatment options available only to patients in wealthier areas of the world.

Overall, 60% of the people going onto ART in the MSF programmes have been women, 94% are ART-naïve, median baseline CD4 cell count 109, and the median follow-up was 10 months. Data on these patients are routinely collected and censored after the last visit going up until December 2006.

The definition of failure used in the programme was based upon WHO guidelines, which required that CD4 cell counts fall to or below baseline values or to half the peak level while responding to treatment, or the onset and development of WHO stage III or IV conditions (serious illness). To be included in the analysis, with the exception of single-dose nevirapine-exposure, participants had to be treatment-naïve when they went on the first-line regimen in the MSF programme. Second line therapy was defined as switching to a protease inhibitor in their ART regimen after at least six months on first-line treatment, (this conservative definition was also used to avoid including the patients who switch regimens due to toxicity rather than failure).

Limitations of the study

Dr Calmy stressed several limitations to this study. Although it may appear as though many patients do not require a change in therapy programme sites used slightly different criteria of failure based upon access to laboratory monitoring. Because of the limited access to viral load, “there is an unknown proportion of patients who would have been on second line based on virological criteria. Evidence suggests that the proportion would have been much greater. Data from South Africa [where viral load monitoring] show that 20% of patients are on a second line regimen,” she said.

Clinicians in the programme may have also been less willing to put patients onto second line ART because of limited access to it. Second line therapy costs 10-15 times more than first line — but cost may not have been the most important factor. Dr Calmy noted that although heat-stable Kaletra would have been a good choice for the PI, it is not registered in many resource-limited countries. Thus most programme sites only had access to the old Kaletra formulation that has to be refrigerated. Nelfinavir, generally thought of as being a sub-optimal PI option, was mostly prescribed “not because of choice but because it requires no refrigeration,” she said.

In addition, clinicians may be reluctant to put someone onto the second-line regimen because it is the last resort in most settings where there is no third-line treatment option. Finally, many patients who should have gone onto second-line treatment may have fallen ill and died before their clinical failure was detected.

Kaletra-based second line ART in the Cambodian programme

In the second study, researchers examined the efficacy of Kaletra-based therapy as 2nd line therapy in a pooled analysis of 113 Cambodian patients.

All patients were followed for a minimum of six months and viral load measurement (>400 copies) and genotypic resistance testing were available in this setting. The median age of patients in this analysis was 38 years. Median CD4 cell count at time of switch was 70 cells and the median viral load (n=79) was 4.7 log copies per ml.

Therapy was changed on the basis of CD4 cell count alone in 30% of the patients and in 70% of patients according to CD4 cell count and viral load. Genotypic resistance was assessed in 52.3%: 91.5% were resistant to 3TC and almost all were resistant to non-nucleoside analogue reverse transcriptase inhibitors.

Patients were switched to Kaletra-based ARV regimens (with a variety of different nucleoside analogue backbones) but the most common combination was Kaletra/ddI/3TC (in 46%). Tenofovir was used by 14.2%.

The median patient follow-up time was 10.1 months — and all patients were still alive at the time of last evaluation.

After six months on second line treatment, the median increase in CD4 cell was 105 cells, and after 12 months, 181 cells —only 3% of the patients had CD4 cell counts remaining below 50 cells. 101 (89.4%) had viral loads

Genotypic testing did not reveal any mutations that would cause resistance to Kaletra. “We found that adherence was the main issue,” said Dr Ferradini. “These patients [who were not responding] were not taking drug at all.”

Based upon the pre-existing resistance to 3TC and many other antiretrovirals at the time of switch, “we have reason to believe that [Kaletra] is doing the job by itself.”

Clinical recommendations

Although the response to second-line therapy in most of the patients was good, despite to long wait to switching, Dr Calmy stressed that to get the best results in patients, “We would like to implement viral load more widely.”

MSF is also greatly concerned about the lack of access to new drugs. “None of the second-line drugs recommended by WHO, except for 3TC and ddI, are currently easily available in resource-limited settings,” said Dr Calmy “Even when we have second-line, we can not foresee that in the next couple years it will come down to the cost of first line. We need generic competition for most of these drugs.”

“Finally,” she concluded “no further options exist for these patients,” and she noted that given changes in patent law in India, it seems unlikely that generics of new antiretroviral drugs or formulations will become available.