Revisiting Monotherapy: Heresy or Revised Orthodoxy?

After the widespread introduction of triple combination antiretroviral therapy in 1996 caused AIDS deaths to plummet, the earlier practice of single-drug treatment -- or monotherapy -- seemed like an embarrassing phase of medical ignorance. By then, it had become all too apparent that monotherapy promoted the rapid development of drug-resistant virus, often leading to treatment failure. Stories still occasionally surface about an isolated doctor prescribing solo AZT (zidovudine, Retrovir), and many long-time HIV physicians with large practices probably have one or two patients still doing well on two drugs and see no reason to change their regimens. But by and large, hitting hard with two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or a non-NRTI (NNRTI) has become dogma, and is now enshrined in all HIV treatment guidelines.

Straying From Dogma

That's why it seemed like heresy -- or lunacy -- when word came in 2003 that a doctor in Houston was conducting a study using only a single boosted drug, the PI combination pill Kaletra (lopinavir/ritonavir), in patients starting their first antiretroviral regimen. (Though Kaletra contains two PIs, it is still considered monotherapy when used alone since the small dose of ritonavir acts solely to enhance the effect of lopinavir.)

Joseph Gathe, MD, took his inspiration from an early Kaletra study showing that the ritonavir-boosted PI could hold its own against combination therapy by suppressing HIV viral load without NRTI support out to three weeks. Other reports had suggested that even when virological control was lost while using Kaletra, resistance mutations were rare. For Gathe, the risk/benefit assessment of treating without an NRTI safety net seemed to be swayed by the non-medical realities of his patients' lives. If dramatically simplifying the regimen meant that his patients could better afford their medicine, have fewer unplanned treatment interruptions, take more of their pills on time, stay adherent longer, and achieve better outcomes, then perhaps straying from dogma was not only justified, but was a wiser clinical judgment.

The problem of affordability was a central issue. With private insurance becoming harder to get and keep, insurance copayments increasing, and government programs tightening access and starting waiting lists, the financial barriers to effective anti-HIV therapy were becoming an undeniable fact of life. So in 2002, with no support from government or industry, Gathe launched a pilot study with 30 patients attending a free clinic in an inner-city Houston neighborhood.

At the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2003, Gathe presented the 24-week results from his study. The aisle in front of his poster was extremely crowded. Much of the curiosity was generated by the fact that he dared to try such a radical strategy at all, while the characteristics of his study population also raised some ethical questions. The average viral load of his participants was over 200,000 copies/mL, and he allowed several individuals with viral loads in excess of 500,000 copies/mL to go on the single-drug plan. The majority also had CD4 cell counts well below 200 cells/mm3. Some felt it was irresponsible to include this vulnerable population in a pilot study.

Yet most who examined the data agreed that single-agent Kaletra had performed well, at least for those who managed to remain in the study. One worrying aspect to the data was the fact that only 22 of 30 patients were still participating at 24 weeks. But the stories of those who left the study served to illustrate the realities that thwart treatment success for so many people with HIV/AIDS. One was deported, another had hepatitis B, and two quit the study due to toxicity. Unemployment and loss of insurance led to treatment failure for one participant who started stretching his medications by taking only one pill daily instead of three. Yet for those who stayed the course, the results were promising, with 95% of those on treatment having viral load suppressed below 400 copies/mL.

A year later, at the XV International AIDS Conference in Bangkok in July 2004, Gathe presented his final 48-week report. At the end of the study, 67% of the original 30 participants had a viral load below 400 copies/mL; no additional patients had disappeared after the initial 24 weeks. Overall, those who managed to stay in the study and stick to their regimens did fairly well. In the end, it was not an unqualified success, but the results focused attention on monotherapy and stimulated a handful of new pilot studies investigating variations on the concept, as well as some larger, more serious trials by Kaletra's manufacturer, Abbott Laboratories.

Gathe has consistently said that monotherapy should not be attempted outside of a clinical trial, and that larger studies for longer periods will be required before conclusions can be drawn about whether Kaletra monotherapy has a place in routine HIV care. But this hasn't stopped individual doctors and patients from attempting this strategy on their own, using solo Kaletra or other boosted PIs, on the basis of theory and the data from this limited study.

While Gathe studied patients who had never been on treatment, most subsequent studies of PI monotherapy have proceeded more carefully by excluding patients with extremely high viral loads or by investigating induction and maintenance as two separate stages, only switching patients to monotherapy after their HIV has been successfully suppressed using a conventional three-drug regimen. Unfortunately, the initial results from these studies have not been overwhelming.

The OK Study

At the International AIDS Society (IAS) conference in Rio de Janeiro in July 2005, José Arribas, MD, reported results from the Abbott-sponsored Only Kaletra (OK) Study; the data were later published in the November 1, 2005 issue of the Journal of Acquired Immune Deficiency Syndromes. This was a randomized, open-label trial of continuing versus stopping NRTIs in 42 patients whose HIV was successfully suppressed on a Kaletra-based combination regimen. At 48 weeks, 95% of those who continued to receive triple combination therapy using Kaletra plus two NRTIs had viral loads below 50 copies/mL, compared with 81% of those taking Kaletra alone. Three patients (14%) in the monotherapy group discontinued due to loss of viral suppression, and one other was lost to follow-up. The only discontinuation in the triple-drug group was due to elevated lipids (blood fats).

The good news is that the Kaletra-only patients who restarted their baseline NRTIs regained viral suppression with no evidence of resistance mutations. A comparison of residual viral load in responders in both arms using an extremely sensitive assay (accurate down to three copies/mL) showed no significant difference between the groups. This suggests that for certain patients, Kaletra monotherapy may work nearly as well as a triple-drug regimen. The challenge is predicting which individuals will benefit from treatment simplification.

Abbott had previously sponsored an 18-person trial looking at switching patients who had achieved viral suppression on a NNRTI-based triple-drug regimen (nevirapine [Viracept] or efavirenz [Sustiva] plus two NRTIs) to a simple maintenance regimen of Kaletra monotherapy. Participants were transitioned from their NNRTI to Kaletra over a two-week period, and then the two NRTIs were discontinued. When Gerald Pierone, MD, reported the 18-week results in 2004 at the Bangkok conference, 14 of 18 participants (78%) remained in the study, and 13 of those had viral loads less than 75 copies/mL. Three of the four who left the study dropped out due to diarrhea and the fourth discontinued when his viral load went above 1,000 copies/mL. In this small study, nearly a quarter of participants would have been better off staying on their original regimens. However, for nearly all of those who continued on treatment, simplification to Kaletra monotherapy led to continued viral suppression.

Kaletra causes gastrointestinal (GI) problems and blood lipid elevations that make it difficult for some patients to tolerate the medication for extended periods of time. [Editor's Note: a new formulation of Kaletra that reportedly produces fewer GI side effects was approved in October 2005; see "News Briefs" in this issue.] Pietro Vernazza, MD, and colleagues with the Swiss HIV Cohort decided to address this issue by switching 24 patients with fully suppressed virus to monotherapy maintenance using boosted atazanavir (Reyataz), a PI that does not raise blood lipids and may be more tolerable than Kaletra. At 24 weeks, 22 of 24 patients in this open-label study continued to have viral load below 50 copies/mL. The study also looked at HIV levels in cerebrospinal fluid and semen. Preliminary results indicated complete or near complete viral suppression in those compartments. However, atazanavir does not enjoy the same reputation for potency that Kaletra does; more evidence is needed to verify whether atazanavir is equally effective in suppressing the virus.

Wave of the Future?

There is still more data to come. Abbott has completed -- but not yet reported -- a 138-person study of single-agent Kaletra versus a conventional Kaletra-based combination regimen. The company limited the entry criteria to people with viral loads less than 100,000 copies/mL and CD4 cell counts above 100 cells/mm3 in this treatment-naive study. Abbott is also sponsoring an ongoing 150-person trial comparing a triple-drug Kaletra-based regimen against a dual-drug combination consisting of Kaletra backed up by tenofovir DF (Viread). This trial, with its extra tenofovir safety net, will take all previously untreated patients with detectable viral load above 400 copies/mm3 and any CD4 cell count (see "Open Clinical Trials" in this issue). Finally, Abbott is planning an induction/maintenance study of Kaletra simplification in people coinfected with HIV and hepatitis C virus (HCV). Meanwhile, back in Houston, Gathe is continuing to investigate his concept with a 40-person open-label study in treatment-naive patients that will run for 48 weeks.

Even if monotherapy proves imperfect in these larger ongoing trials, a limited acceptance of the concept and wider use in practice may still be driven by the factors that initially motivated Gathe. Individuals using private insurance, Medicaid, or AIDS Drug Assistance Programs (ADAPs) might opt for simplification to reduce copayments by one-half to two-thirds -- or may be pressured to do so by third-party payers eager to cut costs. But monotherapy not only reduces financial costs: simplified regimens could also offer reduced toxicity and increased adherence.

If the ongoing studies show that the risk of resistance is low and that viral load can be reliably rolled back by returning to a combination regimen, then many may be tempted to give monotherapy a try. Still, the evidence from the trials in progress will have to be strongly convincing to dislodge the accepted practice of combination therapy that has served so many so well. (One source of resistance could be the pharmaceutical industry, which has a strong incentive to see that the number of drugs required for treating HIV does not shrink from three to one.) If the risks are seen to be acceptable, and catastrophes few, it is possible that monotherapy -- for the right patients, at the right time -- may eventually find a niche as a viable and useful strategy for treating HIV disease.

Another Type of Monotherapy

The use of monotherapy appeared in another study reported at the IAS conference in Rio, although this one did not attempt to maintain viral suppression with only one drug. It has been observed that HIV that has developed resistance to 3TC (lamivudine, Epivir) may be less able to replicate as efficiently as wild-type virus. Some researchers have proposed that continuing 3TC in a regimen even after resistance has emerged could perhaps keep the hobbled HIV in play, thus offering the benefits of a less harmful virus.

Antonella Castagna, MD, and colleagues took this concept one step further and compared the impact of continuing or stopping 3TC monotherapy on the rate of CD4 cell decline in people who had decided to undergo a treatment interruption. The participants all had prior documented 3TC resistance. By 48 weeks after discontinuing their complete regimens, fewer patients who continued to take 3TC alone had experienced a defined failure (an HIV-related symptom or a CD4 count below 350 cells/mm3) than those who stopped everything (44% vs 68%, respectively). The authors concluded that, "3TC monotherapy induces less immunological and clinical failure than treatment interruption."

Bob Huff is editor of GMHC Treatment Issues_, published by Gay Men's Health Crisis in New York City._

Selected Sources

Arribas, J.R. and others. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). Journal of Acquired Immune Deficiency Syndromes. 40(3): 280-287. November 1, 2005.

Castagna, A. and others. E-184V study: lamivudine monotherapy vs treatment interruption in failing HIV-1 infected subjects, harbouring the M184V mutation: 48-week final results. 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro. July 24-27, 2005. Abstract WeFo0204.

Gathe, J.C. and others. Pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV-positive ARV-naive patients: interim analysis of subjects completing at least 24 weeks of a 48 week study. 43rd ICAAC. Chicago. September 14-17, 2003. Abstract 845.

Gathe, J.C. and others. IMANI-1 TC3WP: Single drug HAART proof of concept study: pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV+ ARV-naive patients—interim analysis of subjects completing final 48 week data. XV International AIDS Conference. Bangkok. July 11-16 2004. Abstract MoOrB1057.

McKinnon, J. and others. The level of persistent viremia does not increase after simplification of maintenance antiretroviral therapy to lopinavir/ritonavir alone. 3rd IAS Conference. Abstract WeOa0203.

Pierone, G. and others. Simplification to lopinavir/ritonavir monotherapy from NNRTIbased HAART in HIV-infected patients with complete viral suppression: 24-week interim analysis. XV International AIDS Conference. Abstract TuPeB4595.

Vernazza, P. and others. Viral suppression in CSF and genital tract in ritonavir-boosted "atazanavir-only" maintenance therapy (ATARITMO Study). 3rd IAS Conference. Abstract WeOa0204.