Induction/Maintenance; Hydroxyurea/ddI Therapy in Early Disease
Induction and maintenance is a concept used in chemotherapy for cancer treatment. It is being explored for treating HIV. The idea is that a person can be treated initially with a potent regimen of 3 or 4 drugs; one likely to suppress viral load to below detection and as low as possible. This phase of treatment is called induction. Increasingly, experts are beginning to agree that suppressing viral load to below 400 or 500 copies isn't enough; it appears as though reaching below 50 copies is increasingly becoming the goal. When viral load has been fully suppressed for a continued period of time, the person can enter the maintenance phase. It is uncertain yet how long the induction phase should last. The maintenance phase consists of lessening the potency of the regimen by removing drug(s) from the regimen. Theoretically lightening up the regimen could consist of several options: stopping 1, 2, or 3 of the drugs in a 4 drug regimen; or, stopping 1 or 2 of the drugs in the 3 drug regimen. Application of this concept in treating HIV is being explored for the first time in ACTG study protocol 343.
In ACTG 343, participants will receive open-label indinavir+AZT+3TC. Only those who have been <50 copies consistently for 6 months will be randomized to one of three options: the same regimen, AZT/3TC or indinavir alone. They will be followed closely; viral load will be evaluated weekly. If rebound occurs the person will be placed back on the full original regimen immediately.
It is important to determine if this concept can be successfully applied in treating HIV. The potential benefits of successful maintenance and induction include- (1) the economic costs of long term multi-drug therapy could be reduced, (2) quality of life could improve; individuals would have less side effects, less potential drug interactions, and the compliance requirements are less demanding with a regimen of fewer drugs, (3) access to treatment might improve; many in the USA have restricted access due to the expense of protease inhibitor treatment; access could be improved in nations where economics prohibit or limit access to expensive HIV treatments.
Nevirapine+AZT/ddI. At the St Petersburg Resistance, Eradication and Treatment Strategy Workshop in June 1997, data was presented about 5 individuals who were in the Incas study #1046. In this study, 151 study participants were treatment-naive, with baseline HIV RNA and CD4 of 25,000 copies/ml and 375 cells, respectively. One of the three randomized treatment groups received nevirapine+AZT/ddI. There were 5 individuals in the triple-drug arm who reached <20 copies/ml and who remained <20 copies/ml, despite interrupting or discontinuing ddI from their regimen and continuing only on AZT+nevirapine. When individuals initiated therapy with AZT+nevirapine alone they were unable to adequately suppress viral load.
One individual interrupted ddI therapy at about week 28, restarted ddI after about 8 weeks; and, continues to be on the triple therapy and remains undetectable in follow-up extending out to about 1.5 years. A second person discontinued ddI after 30 weeks and remained <20 copies/ml. They restarted ddI after about 10 weeks off ddI, remained on the triple therapy and remains undetectable in follow-up out to about 136 weeks. A third person (the most interesting case) interrupted ddI therapy at week 20, remained undetectable only on nevirapine+AZT out to 100 weeks and then added 3TC. A 4th person discontinued ddI after about 1 year and remains <20 copies in follow-up out to about 1.5 years. The 5th person discontinued ddI at about 36 weeks, remained <20 copies on only nevirapine+AZT but restarted ddI at about 52 weeks and remains <20 copies. All of these individuals reached < 20 copies/ml prior to discontinuing ddI and remain <20 copies/ml in extended follow-up.
Although the data is based upon a small number of individuals and the study was not designed to address the question, this data caused some present at the meeting to feel it might support the notion that induction/maintenance may be a viable concept.
Hydroxyurea + ddI. Hydroxyurea has been used as an approved treatment for several types of cancer for many years. In the past 2 years it has been getting increasing attention for use as a treatment for HIV. Data from several studies indicate that using hydroxyurea in combination with ddI or ddI+d4T can have an added benefit of suppressing viral load beyond what you would receive from ddI or ddI+d4T without hydroxyurea. Although the use of hydroxyurea for treating HIV is experimental, the data is relatively preliminary, and it is not FDA approved for use in HIV treatment, some individuals who may be resistant to protease inhibitors and nucleosides consider hydroxyurea as a potential therapy option.
In the recent issue of NATAP Reports (July '97) we review the data from the hydroxyurea studies, the mechanism by which hydroxyurea works, and why CD4s do not proportionately increase as from antiretroviral therapy. Usually there is only a slight increase in CD4 and there can be suppression of white blood cells from hydroxyurea therapy. Our web site has an interesting report on how ddI resistance does not prevent hydroxyurea+ddI from being effective (Drug Development section, Post Antiretroviral Conference reports, "Hydroxyurea in combination with ddI or ddI/d4T"). NATAP Reports is available on the web site or you can e-mail us for a printed copy of this and future issues email@example.com
The study discussed in the following report explores the use of hydroxyurea+ddI as a first line therapy for treatment naive individuals, as an eradication therapy (if eradication is possible; it has not yet been proven), or as a therapy that may be useful during primary infection. In fact, the recently reported findings by Dr. Robert Siliciano has created additional doubt about the possibility for eradication. On the NATAP web site is an article just posted discussing lymph tissue penetration by a ritonavir regimen and Siliciano's findings on latently infected cells containing slow decaying proviral HIV DNA.
In the August 30, 1997 issue of Lancet, Jorge Vila et al report in a research letter about a study of hydroxyurea+ddI that addresses the issue of induction/maintenance, whether or not the detected proviral DNA is infectious, the combination's effect on a variety of virus activity measures in plasma and lymph nodes, and the combination's activity in resting cells as a key to its benefit.
2 study participants, whose plasma viral load was undetectable (>200 copies/ml) after one year of therapy with ddI+hydroxyurea agreed to completely stop therapy and remained undetectable at 1 year of follow-up. These two patients started therapy at 3 and 12 months, respectively, after HIV infection. Seropositivity was confirmed by ELISA and western blot. Neither patient had symptoms after infection.
In the Lancet research letter, the authors refer to a different study reported at the Third Antiretroviral Conference in 1996 presented by J Montaner et al where "individuals without symptoms and with virus load stabilized by pre-treatment with ddI had a statistically significant decline in viral load after one month's treatment with the combination of ddI+hydroxyurea."
In this study conducted by Vila, 25 ddI-naive individuals without symptoms with CD4 >200 were treated for up to one year with 200 mg ddI twice daily, and 500 mg hydroxyurea twice daily. Baseline HIV RNA was 29,396 copies/ml.
8 individuals received lymph node biopsies. Investigators said treatment was well tolerated. There were no treatment interruptions due to side effects. There were a few minor transient symptoms such as digestive disorders, and an increase in mean corpuscular volume. After one year, leucopenia (reduction in WBCs) was seen in four patients (three grade 1, and one patient Grade II). No changes in platelets, hemoglobin, amylases, lipases, or LFTs were recorded.
Results. 13/24 and 10/20 individuals suppressed their plasma viral load to undetectable (<200 copies/ml) at 6 months and one year, respectively. Most of these undetectable individuals at one year also had no detectable infectious virus in their lymph node MNCs and CD4s after one year's therapy. The average CD4 increased from 525 to 601 cells, although in other studies the CD4 increase can be slight because hydroxyurea inhibits cell replication. Of the 8 individuals who had their lymph node biopsied, 1/8 had a detectable plasma viral load (1017 copies/ml), undetectable virus in lymph node MNCs, but had detectable infectious virus in their lymph node CD4s; 5/8 had undetectable plasma viral load, and no infectious virus in both their lymph node MNCs and CD4s; 1/8 had undetectable plasma viral load, but had detectable infectious virus in both the lymph node MNCs and CD4s; data was not available for one person.
For the two patients who agreed to discontinue therapy, their baseline plasma viral load was 676 and 1120 copies/ml, respectively; and they had normal CD4s at baseline, prior to receiving study treatment. They both reached undetectable in their plasma HIV RNA by one year on therapy and remained undetectable one year after stopping therapy. As well, extracellular RNA was undetectable after 2 years in both plasma and lymph nodes; and intracellular HIV RNA was below the level of detection (undetectable) in PBMC (peripheral blood mononuclear cells) and LNMC (lymph node mononuclear cells). Culture yielded no infectious virus from either LNMC or purified CD4 t cells.
Baseline proviral DNA in the PBMCs (peripheral blood MNCs) were 654 copies/106 cells in patient A and 65 copies/106 cells in patient B. At both 1 and 2 years proviral DNA was non-quantifiable in patient B, and marginally detected in patient A. Qualitative evaluation of proviral DNA at 2 years in PBMC showed low levels for both patients but it "seems" to be non-infectious or incompetent for the release of infectious virions. Proviral DNA was found at low levels in both patients LNMC at 2 years. However, other researchers believe that although some proviral DNA may be defective there is a pool of proviral DNA that is replication competent. The researchers in this effort may have not found the replication competent proviral DNA.
Investigators concluded that "an explanation for the absence of viral rebound (for the 2 patients who stopped therapy) could be that this combination may exercise its anti-HIV activity in resting cells". Resting cells are an important reservoir for proviral DNA. It has been suggested that ddI, as well as 3TC and ddC, work in resting cells, while d4T and AZT work in activated cells. Hydroxyurea's mechanism of action may, theoretically, increase the chances of ddI in terminating the successful growth of proviral DNA competent to produce infectious virus. Furthermore, the authors say these findings suggest that the combination of ddI and hydroxyurea may be applied for potential eradication in early disease.
Bristol Myers Squibb has started three trials exploring hydroxyurea in HIV treatment. A large trial comparing ddI+d4T to hydroxyurea+ddI+d4T in 200 individuals with 200-500 CD4s started in December 1996. The second trial of 20 individuals will explore a 4-drug regimen of nelfinavir+ddI+d4T+hydroxyurea in individuals with >500 CD4. The third trial will explore the potential for eradication in 20 individuals during primary infection with the same 4-drug regimen: nelfinavir+ddI+d4T+hydroxyurea.