Structured Treatment Interruption
Part II: Case Studies

Coverage provided by Gerald Pierone Jr., M.D.

February 14, 2004
Part I: Overview
Case Study 1
Case Study 2
Case Study 3
Case Study 4
Case Study 5
References

Despite their generally experimental nature, structured treatment interruptions (STIs) are fairly common, and there may be a trend for even more STIs in HIV clinical care in the future. For example, the important Swiss HIV observational cohort tracks, among other things, HIV treatment status. In this cohort, 7.6% of patients were on HIV treatment interruption in January 1999. However, as of January 2003, 14.8% were in this category.1

Some STIs are, in fact, patient initiated, and the clinician learns about the situation after the fact. In other cases, the determination to initiate an STI is a shared decision that is often based on an attempt to mitigate medication-related toxicity. The following four case studies represent a variety of STI scenarios that might be encountered in practice. These case presentations should not be construed as an endorsement of STI, but rather as a reflection of some of the reasons for STI and its potential outcomes.

Case Study 1
A 38-year-old, gay male was diagnosed with HIV infection in April 1996. He presented with AIDS dementia complex and was found to have a CD4 count of 61 cells/mm3 and a viral load of 78,000 copies/mL. He was begun on a combination of stavudine (d4T, Zerit), lamivudine (3TC, Epivir) and indinavir (IDV, Crixivan) and demonstrated an excellent virologic and immunologic response. Two months into therapy, his CD4 count increased to 284 and his plasma HIV-RNA was less than 250 copies/mL. The findings of neurocognitive dysfunction gradually improved, eventually resolving completely after several months.

He remained on the same regimen of stavudine, lamivudine and indinavir until January 2000; his CD4 count was 826 cells/mm3 and his plasma HIV-RNA was less than 50 copies/mL. At that time, progressive obesity and abdominal visceral fat hypertrophy were noted and nevirapine (NVP, Viramune) was successfully substituted for indinavir. In 2001, a diagnosis of hypogonadism was made and testosterone replacement therapy was begun. He was also diagnosed with hypertension, which was treated with atenolol (Tenoretic, Tenormin) and enalapril (Vasotec).

In August 2001, his viral load was less than 50 copies/mL, his CD4 count was 725 cells/mm3 and his serum testosterone level was normal. Because of complaints of fatigue and malaise, and after discussion with his clinician, he elected to interrupt antiretroviral therapy. Two weeks after he stopped treatment, he developed a sore throat and headaches. Sinusitis was suspected and he was begun on azithromycin (Zithromax). There appeared to be transient improvement, but four weeks after he stopped treatment, he developed fevers accompanied by cervical lymphadenopathy and worsened fatigue. Despite empiric therapy with levafloxacin (Levaquin) for suspected sinusitis, within several days the headaches worsened and he developed encephalopathy along with a high fever and he was admitted to the hospital.

A brain computed tomography (CT) scan was negative for mass lesion. A lumbar puncture was performed and there were 250 white blood cells, 86% of which were lymphocytes. Cerebrospinal fluid protein was 85 mg/dL and glucose 56 mg/dL. He was treated empirically with ceftriaxone (Rocephin) and corticosteroids. The fluid rapid plasma reagin (RPR) was negative as were the bacterial cultures. A diagnosis of aseptic meningitis was made; ceftriaxone treatment was stopped and corticosteroid treatments were tapered off. His CD4 count was 301 cells/mm3 (21%) and his plasma HIV-RNA was 24,800 copies/mL.

After he was discharged from the hospital, he was started on zidovudine (ZDV, Retrovir) + lamivudine (ZDV+3TC, COM, Combivir) and efavirenz (EFV, Sustiva, Stocrin). He developed a rash from the efavirenz and the regimen was changed to zidovudine + lamivudine + abacavir (ABC, Ziagen) (ZDV+3TC+ABC, Trizivir). He tolerated the therapy well and there was a gradual resolution of the headaches and fatigue. In October 2001, his viral load was again undetectable and his CD4 count had increased to 514 cells/mm3. Subsequently, he experienced viral breakthrough with the development of resistance to zidovudine + lamivudine + abacavir. Currently he is on zidovudine + lamivudine + abacavir and tenofovir (TDF, Viread) and is clinically stable.

Discussion
This patient had acute retroviral syndrome or retroviral rebound syndrome, a potential complication of a STI.2 Some patients who discontinue therapy will develop a viral-type syndrome that, on occasion, may be quite severe. In this case, the aseptic meningitis was likely related to recrudescent HIV infection following years of quiescence created by effective HAART. Studies of primary HIV infection have shown that approximately one third of patients present with aseptic meningitis as a component of their illness.3

However, the risk of acute retroviral syndrome during an STI appears to be low, generally less than 5%, depending on which study is referenced. In the BASTA study,4 acute retroviral syndrome occurred in two of the 76 subjects in the STI group with the first STI, but not on subsequent interruptions. In the SSITT study, there were two cases of acute retroviral syndrome among the 133 subjects,5 although the short treatment interruption of only two weeks may have reduced the likelihood of this event. Thus, the overall risk of a retroviral rebound is low, but when it occurs, symptoms may be quite severe.

Case Study 2
A 58-year-old, male hemophiliac was diagnosed with HIV infection in 1993. His CD4 count was 350 cells/mm3 and therapy was commenced with zidovudine monotherapy. The course was complicated by anemia and treatment was placed on hold.

In 1996, he was given stavudine, lamivudine and indinavir. Subsequent viral load determinations were below the level of detection and his CD4 count improved and ranged around 500 cells/mm3 over the next several years. The course was complicated by the development of painful sensory neuropathy and he was treated with amitriptyline (Elavil, Endep).

Despite the use of amitriptyline, his neuropathy worsened and eventually stavudine was stopped and delavirdine (DLV, Rescriptor) was substituted. The neuropathy continued to be poorly controlled and he was begun on controlled release morphine (Kadian, MS Contin, MSIR, Oramorph SR, RMS, Roxanol, Roxanol 100). Because of this chronic pain and the sedation caused by the pain management narcotics, he retired from work.

He developed progressive abdominal protuberance, post-prandial bloating and weight gain in 2001, which responded to neither diet nor exercise. His viral load was undetectable and his CD4 count was 488 cells/mm3. The decision was made to discontinue his antiretroviral medications. Within several weeks his bloating improved and over the next several months his abdominal protuberance began to recede. His plasma HIV-RNA has remained below the level of detection from 2001 to January 2004 and his CD4 count has fluctuated between 300 and 400 cells/mm3. EIA for HIV and Western Blot testing have been repeatedly positive.

Figure 1: Plasma Levels of HIV-RNA in Case Study #2

Plasma levels of HIV-RNA were measured using a branched-chain DNA assay with a limit of sensitivity of 500 copies per milliliter. Day 0 was the first day of treatment. Shaded areas indicate periods of no treatment.

Discussion
This unusual case demonstrates that rare patients treated with HAART are able to maintain virologic control even after antiretroviral therapy is withdrawn. This phenomenon was first described in 1999 with the example of the "Berlin" patient,6 a patient who had been started on antiretrovirals during acute infection and had therapy temporarily stopped on two occasions. When his therapy was stopped altogether, he maintained long-term viral suppression.

In this present case, our hemophiliac patient was probably not treated during acute HIV infection. In addition, we did not have a baseline viral load prior to initiating antiretroviral therapy since he had been started on HAART in 1993 -- before HIV-RNA testing had become commercially available. It is possible that he may have had a favorable prognosis with low viral load prior to starting antiretroviral therapy, although he did have a fairly low CD4 count and percentage reflecting enough viral activity to lead to immune damage.

As mentioned, the impetus for this patient's treatment interruption was directly related to antiretroviral toxicity, including the severe painful peripheral neuropathy from stavudine that had led to his subsequent early retirement. Gastrointestinal side effects and progressive abdominal protuberance also were responsible for his treatment interruption. Once therapy was stopped, all these symptoms significantly improved. An added and unexpected bonus of this STI has been this patient's prolonged time off therapy with an undetectable viral load and stable immunologic function.

It is unclear why the rare patient with HIV infection is able to maintain long-term virologic control after treatment interruption. This case, also atypical, was presented to highlight the fact that unexpected observations may stimulate investigation into new areas and sometimes lead to a better understanding of disease states. Just as the "Berlin" patient led to research interest into STI for acute HIV infection, study of cases like this may clarify the mechanisms of virologic control with STI after long-term treatment in chronically infected patients. Ongoing STI studies such as "SMART" will provide some answers as to the frequency of virologic control after STI in chronic infection. However, at this point, there is no way of predicting which patient will be able to maintain virologic control after stopping. In the meanwhile, anecdotal cases like this one continue to tantalize clinicians and sustain interest in STI.

Copy right by HIV Institute Royal Organiztion 2005