Structured treatments interruptions

30 July 2001. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 15 Sitges 2006.

Paul Blanchard, HIV i-Base

A number of presentations at this meeting provided additional data concerning STIs (Structured Treatment Interruptions).

STIs, viral reservoirs, viral evolution and 3TC resistance

Cecile Tremblay from Massachusetts General Hospital presented data on repeated STIs in early antiretroviral treatment of acute infection. [1] The group intended to determine the effect of STIs on replenishment of viral reservoirs, viral evolution and emergence of drug resistance. Quantitative enhanced HIV culture [2] was performed before STI when viral load was <50 copies/mL and again after therapy was restarted and plasma viral load was again below 50 copies for at least one month. Sequencing was performed at baseline, 1st rebound and 2nd rebound and phylogenetic analysis determined.

Results revealed no increase in the level of infectious HIV recovered from PBMC’s following an STI in any of the seven subjects studied. In fact, a greater than 3-fold decrease in this viral reservoir was observed in four of seven subjects. In two subjects, rebounding virus showed some evidence of viral evolution from the first to second STI. The initial emergence of 3TC resistance mutation 184V was observed during an STI in one of 14 subjects.

These data are reassuring in terms of the effects of STI on viral reservoirs and the limited viral evolution seen during an STI. The emergence of 3TC resistance in one subject is of some concern. The group hypothesised that this may be due to the prolonged intracellular half-life of 3TC triphosphate in comparison to that of other components of the regimen.

A separate poster also reported selection of the M184V mutation in 2 of 12 patients at the end of a 2nd and 3rd STI. [3] In contrast to the subjects in the Tremblay study, however, these were chronically infected patients who had previously received regimens containing 3TC before starting HAART. The presenter, Javier Martinez-Picado, concluded that consecutive STIs may promote selection of drug resistant virus present as minor populations prior to STIs.

STIs and NNRTI resistance

Selection of NNRTI related resistance mutations during STIs has been a theoretical concern due to the long half life of these agents. Some clinicians have suggested either that NNRTI-containing regimens are unsuitable for STIs or that the NNRTI should be stopped in advance of the other regimen components. Observational data on seven patients receiving NNRTIs (3 efavirenz, 4 nevirapine) and performing STIs was presented by Lidia Ruiz from Barcelona. [4] The treatment interruption strategy consisted of 2 weeks off and 4 weeks on therapy.

NNRTI-related mutations were not detected in either plasma RNA nor in PBMC DNA in any of the seven subjects receiving NNRTIs. Zidovudine resistance associated mutations were detected in DNA samples from one patient who had received zidovudine for 5 years before their current antiretroviral regimen. The researchers concluded that short STIs in patients with prolonged undetectable viral load (<50 copies/mL) on NNRTI therapies do not cause the emergence of virus resistant to NNRTIs. They also observed that the reintroduction of HAART containing nevirapine after short STIs did not cause rash or other side-effects and that dose modification of nevirapine did not appear to be required after short STIs.

HIV specific immunity: effects of STI’s in chronically infected patients

The immune effects of STIs were investigated by the Fundacion irsiCaixa, Barcelona. Lidia Ruiz presented data on HIV-specific CD8+ T-cell responses and viral load rebounds in chronically infected patients after four STI’s. [5] 12 patients performed STIs consisting of 4 weeks off and 12 weeks on therapy. After the fourth STI cycle antiretroviral treatment was discontinued until plasma viral load reached >50,000 copies/mL and/or CD4 counts dropped below 350 cells/mm3. Five of the STI patients were receiving HAART + IL-2, the other 2 patients HAART only. IL-2 was administered during the periods of therapy.

Results revealed that for 10 patients who underwent five STIs, viral load rebound was observed in at least one of the interruptions. Five of the ten patients reinitiated HAART due to viral load increases >50,000 copies/mL whereas the other five remaining patients continue without HAART. Percentage and absolute T-cell numbers did not vary significantly during the first four short treatment interruptions. However, a significant median fall in CD4 of 548 cells/mm3 occurred during the last stop off therapy. Three out of ten patients had an increase in HIV-specific CD8+ cell frequencies.

Ruiz concluded that controlled exposure to HIV antigen during STIs produced an increase in HIV-specific CD8+ T-cell responses in 30% of chronically infected patients. This STI strategy also appeared to control viral replication in a limited number of patients for at least 3 months. However, a substantial decline in CD4 count occurring after 3 months off therapy warrants caution.

Hydroxyurea and STIs

The use of hydroxyurea (HU) during STIs was explored in a presentation by Jose Gattell. [6] An analysis of a randomised study was presented to determine if the association of HU with STIs could help to control HIV replication after cyclic interruption of HAART without deleterious effect on HIV-specific immune responses.

Twenty chronically infected patients with CD4 counts >500 cells/mm3 were treated with d4T/ddI/indinavir for 52 weeks. Plasma viral load was <20 copies/mL for at least 32 weeks. These 20 subjects were randomised to continue the same combination (n=10) or to add HU (n=10) during the following 6 months. All subjects then performed five cycles of STI.

Each interruption of therapy was separated by periods of 2 months with the same regimen. HAART was reintroduced if viral load increased >200 copies/mL in the 1st stop, after 2 weeks in the 2nd, 3rd and 4th stop, and after viral load reached a set point after the 5th stop. HU was discontinued along with HAART in the 1st, 2nd and 3rd stops but was maintained in the 4th and 5th stop.

Results were presented for 17 patients (16 in the abstract) who had reached at least 6 months off therapy after the fifth stop. A rebound in viral load was detected in all cases in all the stops, even when HU was maintained. There were, however, differences observed between the two groups as seen in the table below

Table: follow-up after stop 5

Mean doubling time of viral rebound was also seen to increase from the first to the last stop, 2.08 to 6.2 days (p=0.05) in the HU group and 3.3 to 5.6 days in the HAART only group (p=0.05) without differences between the groups. HIV specific CD4+ lymphocyte responses increased from the 1st to last interruption from 0/10 to 2/9 patients in the HAART group and from 0/10 to 6/7 patients in the HU group. CD4 T-cell counts did not drop below 500/mm3 in any patient.

The group concluded that immunosuppressive therapy (in this case hydroxyurea) may increase the percentage of patients able to achieve control of viral replication (<5,000 copies/mL) after cycles of STI and a long period off therapy. Hydroxyurea associated with HAART and maintained during periods of interruption and the period off therapy did not adversely affect either HIV-specific helper or CTL responses.

References:

1. Tremblay C, Hicks J, Sutton L et al. HIV evolution during repeated supervised treatment interruptions following early antiretroviral treatment in acute infection. Antiviral Therapy 2001; 6(Supplement 1):17. Abstract 19.
2. Tremblay et al. JCM 2000; 38:4246-8.
3. Martinez-Picado J, Morales-Lopetegi K, Wrin T et al. Selection of the M184V mutation during repetitive cycles of structured antiretroviral treatment interruptions. Antiviral Therapy 2001; 6(Supplement 1):28. Abstract 36.
4. Ruiz L, Romeu J, Martinez-Picado J et al. Structured treatment interruptions in HIV-infected patients on non-nucleoside reverse transcriptase inhibitor-based therapies. Antiviral Therapy 2001; 6(Supplement 1):90. Abstract 122.
5. Ruiz L, Martinez-Picado J, Marfil S et al. Distinct HIV replication outcome after four structured treatment interruptions in chronic HIV-infected patients. Antiviral Therapy 2001; 6(Supplement 1):30. Abstract 40.
6. Garcia F, Plana M, Ortiz GM et al. Immunosuppressive therapy with hydroxyurea can improve the efficacy of structured treatment interruption in chronic HIV-1 infection: a pilot randomised study. Antiviral Therapy 2001; 6(Supplement 1):25. Abstract 31.