American Foundation for AIDS Research, May 2003
Gretchen Schmelz Armstrong

Structured treatment interruptions — in which patients cycle on and off therapy for days, weeks or months — once again occupied center stage at the 10th Conference on Retroviruses and Opportunistic Infections. Attendees heard reports from more than a dozen STI studies in chronically infected individuals. The 48-week results offer tantalizing clues to the perfect drug vacation schedule, which would minimize drug toxicities without undue penalties in terms of CD4 count decline, viral load rebound, or increased HIV drug resistance. At the same time, little now remains of the original hope that HIV replication during STIs could wean patients off therapy forever by provoking effective antiviral therapy.

CD4-Guided Strategies: A New Wrinkle
Jintanat Ananworanich (Thai Red Cross AIDS Research Center, Bangkok) presented data from the prospective HIV-NAT 001.4 study. The 74 heavily treatment-experienced patients had spent a year on suboptimal dual nucleoside analog therapy followed by three years on a protease inhibitor-based regimen. Upon entering the study, they had viral loads of less than 50 copies/mL and CD4 counts above 350 cells/mm³. Participants were randomized to one of three arms. The "continuous" arm received ritonavir-enhanced saquinavir plus two nucleoside analogs without interruption. In the "CD4-guided" arm, study participants began therapy when their CD4 counts dipped below 350 cells/mm³ (or 30% below their baseline count). Those in the "one-week on, one-week off" arm stopped and started treatment every seven days, regardless of CD4 counts or viral load.

No one experienced disease progression, and the percentage of those with CD4 count above 350 cells/mm³ was similar in the continuous and week-on, week-off arms (100% vs. 96%, respectively). Those in the CD4-guided arm experienced an average 178 cells/mm³ drop in CD4 count, with 87% still having a CD4 count above 350 cells/mm³.

Despite the overall figures, serious problems did arise in the week-on, week-off arm. Eight of the 26 failed treatment, defined as a viral load above 1,000 copies/mL (in seven of the eight) or, in one case, a CD4 count below 350 cells/mm³. This arm was cancelled as a result, and everyone in the group resumed therapy. Although all were able to suppress viral load within three months, resistant virus had emerged in some patients.

A Spanish STI study also examined intermittent CD4-guided therapy versus continuous treatment. Lidia Ruiz (Fundació Irsi Caxia, Barcelona) presented this research. The 122 chronically infected volunteers had good virus suppression (less than 80 copies/mL for at least a year and CD4 counts above 500 cells/mm³ for six months or more). People assigned to the CD4-guided arm could restart therapy if their viral load increased to above 100,000 copies/mL; their CD4 count dropped below 350 cells/mm³; or an opportunistic infection appeared. They stopped therapy if their CD4 count climbed above 500 cells/mm³ and viral loads decreased to below 80 copies/mL.

The baseline CD4 counts were about 825 cells/mm³ at the start of the study. Forty-eight weeks later, CD4 counts remained stable and viral loads undetectable in all but two volunteers on continuous therapy. In the CD4- and viral load-guided arm, 35 of 59 volunteers (57%) had to restart their medication. Participants in this arm lost, on average, 96 CD4 cells/mm³ each month. Twenty-six volunteers (43%) were able to remain off therapy the full 48 weeks, although their CD4 counts decreased by an average 335 cells/mm³ (their average viral load was about 13,000 copies/mL). One side effect that occurred in 6 people (10%) in the CD4- and viral load-guided arm was a flulike acute retroviral syndrome, similar to what occurs when first contracting HIV.

Resistance is Always a Formidable Risk
Although the investigators of the Spanish study did not document resistance, this is always a possibility when virus rebounds. Resistance data was the focus of the early safety analysis of PART, a 273-person study that assigned volunteers to either a continuous treatment arm or an intermittent arm. Stefano Vella (Instituto Superiore di Sanita, Rome) presented the results of the first three of the planned five cycles. During this time, most people (89% in the continuous arm and 97% in the intermittent arm) suppressed virus below 400 copies/mL. When the investigators looked for resistance in these patients after three cycles, they found that 24% had at least one resistant mutation. Half of these persons had at least one mutation when they entered the study. The investigators also noticed that when the STI arm was divided based on the presence or absence of mutations, there was a trend toward a slightly lower response rate to treatment in the group with mutated HIV.

Resistance was the reason a "long cycle" STI study closed early to enrollment. Patients assigned to the intermittent arm stayed off therapy for a month and then went back on for two. The other half was assigned to take treatment continuously. Five people in the intermittent arm developed resistance to protease inhibitors, efavirenz or 3TC. Moreover, when the investigators looked at 48-week lipid levels, liver function and C-reactive protein (an important marker for heart disease), they could only find a transient decrease in triglycerides at week 40. Mark Dybul (National Institute of Allergy and Infectious Diseases, Bethesda, MD) presented the study. He was not surprised that these levels, which measure drug toxicity, were similar between groups. "If you are on your drugs for two months, your levels are going to increase. We did see a decrease at week 40 [in triglycerides], and one could argue that these transient decreases matter. But what’s disturbing is that the marker for heart disease — C-reactive protein — did not decrease."

STIs for Deep Salvage
The most controversial aspect of STIs is whether they are an appropriate strategy for people with multi-drug resistant HIV and few treatment options. A treatment interruption in this case might allow for the reemergence of drug-sensitive HIV. But an STI carries health risks from rebounding HIV.

The first was the CPCRA 064 trial, which immediately switched enrollees to a different regimen or waited four months and then switched them. Mean baseline viral load was 100,000 copies/mL, and the mean baseline CD4 count was 180 cells/mm³. The regimens were individually optimized based on resistance testing of a study participant’s HIV. The average number of drugs was 3.8, and in both arms, viral load drops of around 85% were achieved after one month or more of treatment.

This 270-person study stopped recruiting more volunteers because 22 patients in the STI arm either experienced a progression in their HIV disease or died, compared with 12 patients who did so in the continuous-therapy arms.

A much smaller study, led by Christine Katlama (Hôpital Pitié-Salpétrière, Paris) evaluated 70 people in the GIGHAART ANRS 097 Trial. The investigators randomly assigned everyone to one of two arms. In the first, patients immediately began a "GIGHAART" regimen (consisting of three to four nucleoside analogs, an NNRTI, hydroxyurea and four protease inhibitors). In the second arm, people began the regimen after a two-month STI. Average baseline CD4 count and viral load were those of advanced AIDS — 27 cells/mm³ and 200,000 copies/mL.

The STI did result in more drug-sensitive HIV. After 12 weeks on treatment, there was a 1.91 log (98.7%) viral load drop in the STI group compared with a 0.37 log (57%) drop in patients on continuous treatment. This effect had diminished considerably after 48 weeks on treatment. The viral load declines from baseline in the STI and continuous arms were, respectively, 0.79 and 0.37 log (84% and 57%). These figures are for everyone in the trial, though at this point only 22% of the continuous therapy group and 47% of the STI group was still receiving GIGHAART regimens. Such a large regimen is very difficult to maintain due to its high toxicity and onerous dosing schedules.

Too Brief an Idyll
"We have some positive data, and some negative data, so we need to study this more," said Stefano Vella. Much more needs to be ironed out as clinicians search for the perfect STI model. There are obvious setbacks to STIs: drug resistance, acute retroviral syndrome, and CD4 cell loss. But HIV-NAT 001.4 was able to show that volunteers in the CD4-guided arm received therapy for only a third of the time compared with controls for up to one year. "The issue of the STIs is always the long-term effects," continued Vella. "That’s why we need long-term studies; without them, we have partial results. The follow-up of many trials is always so short. We treat patients for years, not months." As researchers continue to search for the safest STI strategy, they may be able to fulfill the hope of less toxicity and less cost.

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