Structured Treatment Interruption
Part II: Case Studies

Case Study 3
In March 2001, a 25-year-old male was diagnosed with AIDS when he was found to have pneumocystis carinii pneumonia. At that time, his CD4 count was 43 and his viral load was 280,000. He commenced a regimen of lopinavir/ritonavir (LPV/r, Kaletra), zidovudine and lamivudine. Over the next two years of therapy, his viral load became undetectable and his CD4 count gradually rose to greater than 500 cells/mm3.

In October 2003, he complained of worsening nausea, anorexia, diarrhea and profound fatigue. As a result of these symptoms, he was taken off antiretroviral medications. Within two weeks, his gastrointestinal symptoms largely subsided, but the fatigue continued. A repeat viral load test eight weeks after therapy interruption showed that his viral load had risen to 75,000 copies/mL and, simultaneously, his CD4 count had dropped to 220 cells/mm3.

He was put back on treatment, with a regimen of once-daily ritonavir (RTV, Norvir), atazanavir (ATV, Reyataz), lamivudine and tenofovir. Eight weeks after resuming therapy, he was tolerating the medications well and a repeat viral load test showed <75 copies/mL and his CD4 count had increased to 350 cells/mm3.

Discussion
This case illustrates the point, now observed in multiple cohort studies,5 that individuals with a low nadir CD4 count and high viral set point are generally not able to stop therapy for long periods.

This patient had a crescendo pattern of worsening gastrointestinal side effects that quickly resolved after treatment interruption. However, virologic and immunologic parameters also quickly deteriorated and led to early resumption of treatment.

This STI provided an opportunity for this patient to change to a new regimen with the hope of better tolerability and continued virologic control. One of the more common errors in the management of HIV is the continuation of an antiretroviral regimen in the presence of ongoing toxicity. Because of the aversive effect of medication-related toxicity, continuation of such treatment increases the likelihood of poor adherence. Clinicians should keep in mind that a patient's quality of life is compromised by forging ahead with a regimen in spite of progressive toxicity, which will certainly affect treatment compliance. There are now more than 17 approved antiretroviral agents, and except for patients who have multidrug-resistant virus, it will almost always be possible to individualize therapy somewhat and construct a well-tolerated regimen.

Case Study 4
A 51-year-old male was diagnosed with HIV in 1989. He started antiretroviral therapy in 1992 and received, in sequence, zidovudine monotherapy, dual nucleosides and ultimately a triple combination of zidovudine, lamivudine and indinavir.

In 1998, his regimen was modified to zidovudine + lamivudine, ritonavir and indinavir and this was continued to January 2003. In 1997, his CD4 count was 197 cells/mm3 and by January 2003 had increased to 538 cells/mm3. His plasma HIV-RNA had been consistently below the level of detection for years.

However, this patient was obese, hypertensive and smoked two packs of cigarettes daily. On antiretroviral therapy, his lipid levels had progressively increased:

September 1998: cholesterol 146 mg/dl, triglyceride 372 mg/dl

December 2001: cholesterol 290 mg/dl, triglyceride 1049 mg/dl
In June 2002, he had an acute myocardial infarction that led to an angiogram and the placement of a left anterior descending stent. He was begun on clopidogrel (Plavix), aspirin (Alka-Seltzer, ASA, Ascriptin A/D, Aspergum, Bayer, Bufferin, Easprin, Ecotrin, Empirin), atorvastatin (Lipitor), atenolol and ramipril (Altace), and reduced his smoking to five cigarettes per day. Despite these measures, in January 2003 his cholesterol was 530 mg/dl and his triglycerides 3,180 mg/dl. He was also diagnosed with diabetes mellitus in January 2003, with a fasting blood glucose of 164 mg/dl and a hemoglobin A1C of 7.3 mg/dl. He developed recurrent angina and oral nitrates were added to his regimen.

In February 2003, he moved from Boston to Florida in the hopes a warmer climate would improve his health.

On Feb. 27, 2003, his cholesterol was 368 mg/dl and his triglycerides were 2,375 mg/dl. Antiretroviral therapy was discontinued and, with no other changes in the regimen, on March 27, 2003 his cholesterol was 82 mg/dl and his triglycerides were 368 mg/dl. The daily episodes of angina resolved within one week of stopping antiretroviral therapy.

In June 2003, he experienced a cerebellar ischemic stroke related to basilar artery atherosclerosis. The resultant ataxia precluded him from riding his motorcycle for several months. He improved with physical therapy, has quit smoking and is clinically stable. He is currently on an STI with a plasma HIV-RNA in the 100,000 copies/mL range and has a CD4 count in the 250 cells/mm3 range.

Discussion
This case provides a rather dramatic example of the potential adverse metabolic effects of antiretroviral therapy in a patient with multiple risk factors.

Protease inhibitors (PIs) in particular have a substantial impact on metabolic parameters.7 Lipid elevations and insulin resistance are commonly seen, especially with indinavir and lopinavir/ritonavir-based therapy. One of the advantages of the newly released PI, atazanavir, is its neutral effects on lipids.8

However, NRTIs also influence lipids. Recent studies have shown that stavudine increases cholesterol and triglycerides much more than tenofovir.9 Nonnucleosides also demonstrate differences in lipid effects; nevirapine increases high-density lipoprotein (HDL) cholesterol more than efavirenz and produces a more favorable total cholesterol:HDL cholesterol ratio.10

We now know that the metabolic impact of therapy should always be considered when making treatment decisions for an individual patient. In this case, despite multiple risk factors and demonstrated severe hyperlipidemia, this patient had never been treated with an NNRTI-based regimen. Several recent studies demonstrate the safety and effectiveness of switching from PI-based regimens to either NRTIs or NNRTIs in order to improve lipids.11 A PI to NNRTI switch strategy may also lead to improvements in insulin resistance and diabetes control.12 When patients develop significant hyperlipidemia or diabetes on PI-based therapy, it is appropriate to switch to a different regimen with less potential for metabolic side effects.

We are still learning about the adverse metabolic effects associated with antiretroviral therapy, which appear to be associated with higher rates of atherosclerosis and adverse cardiovascular outcomes. The D:A:D study, a large, prospective cohort of over 23,000 HIV-infected patients, demonstrated a 26% increased risk of myocardial infarction per year of exposure to antiretroviral therapy.13 And since many patients with HIV also have risk factors for heart disease, like obesity, smoking, family history of heart disease, this will be a continuing problem.

Case Study 5
A 25-year-old, gay male with multiple previous negative HIV tests went on vacation and, during a weekend of heavy cocaine use, had unprotected intercourse with multiple partners. Two weeks later, he developed a severe viral type illness characterized by headache, conjunctivitis, fever, anorexia and diarrhea. He promptly sought medical attention. An HIV antibody test was negative, but a quantitative plasma HIV-RNA came back positive at >500,000 copies/mL and he had a CD4 count of 489 cells/mm3.

Several weeks later he visited an HIV specialist and the decision was made to initiate antiretroviral therapy. Immediately prior to starting treatment, his plasma HIV-RNA was 57,000 copies/mL, his CD4 count was 460 cells/mm3, and an HIV genotype showed wild-type virus. A regimen of tenofovir, lamivudine and efavirenz, with all medications taken together at bedtime, was commenced. He tolerated the medications well except for morning dizziness and a "hung over" feeling that gradually improved and, after two weeks, resolved completely.

Follow-up testing at week 4 showed that his viral load had dropped to 640 copies/mL and his CD4 count was 610 cells/mm3. By week 8 his plasma HIV-RNA level was undetectable and his CD4 count was 723 cells/mm3. A repeat HIV EIA and a Western Blot confirmatory test were positive. At this time, he had unprotected intercourse with an HIV-positive individual who was on antiretroviral therapy, but with incomplete viral suppression. The new sexual contact had a plasma HIV-RNA that had recently been measured at 1,000 copies/mL, but no resistance testing was available. Because of this second exposure, the original plan to stop HAART was postponed, and therapy was continued for an additional month before it was discontinued.

He had received a total of 12 weeks of continuous antiretroviral therapy before the discontinuation. Four weeks after stopping treatment, his plasma HIV-RNA remained undetectable, although eight weeks later it rebounded to 1,200 copies/mL. From a clinical perspective, he was asymptomatic. After an additional eight weeks, his viral load was 800 copies/mL and, during this time off medications, his CD4 count ranged from 600 to 750 copies/mL. The patient and his clinician planned to monitor his course off antiretroviral therapy and consider restarting if his viral load showed a consistent increase above 5,000 copies/mL.

Discussion
In this case, prompt diagnosis of HIV infection in a patient at high risk led to early treatment with HAART. Notably, even before initiation of antiretroviral therapy, there was a reduction in viral load from >500,000 copies/mL to 57,000 copies/mL. This aspect of the case highlights the ability of HIV-specific immune responses to gain some measure of control over viral replication. For this patient, commencement of combination antiretroviral therapy led to rapid virologic control and improvement in his CD4 count.

After three months of HAART, treatment was suspended as part of a planned STI strategy. In the short term, this patient has done well with plasma HIV-RNA levels remaining relatively low off therapy. Of course, it is impossible to know whether this patient would have ended up with a similarly low viral load had he not initiated HAART early.

Much of the interest in STI was generated from early positive results found in observational case studies in patients with primary HIV infection. Although it is estimated that about 40,000 new cases of HIV infection occur in the United States each year, the great majority are not diagnosed during the early acute phase. Some patients are not diagnosed early because the infection is silent, but the non-specific nature of findings in those with symptomatic infection and a low index of suspicion among front-line clinicians also contribute to misdiagnosis.

Also, the shift in the epidemic towards the heterosexual and minority populations accounts for some of the challenges in establishing an early diagnosis. Many of those currently at risk for HIV infection do not perceive themselves to be at risk, and present to emergency departments or urgent care centers that are not equipped for HIV counseling and testing. Moreover, sometimes when HIV is considered in the differential diagnosis and testing is ordered, only an antibody test is performed and not a test to measure viral replication and thus the diagnosis may be missed. As this case illustrates, the early diagnosis of primary HIV infection before seroconversion depends on measuring HIV-RNA.

For the rare few who are diagnosed with primary HIV infection there are no clear answers on the most appropriate management. Based on positive reports from early STI studies in primary HIV infection,14 some clinicians will recommend a similar approach. The hope is that prompt treatment may curtail widespread dissemination of HIV and that STI may lead to some degree of autoimmunization. However, recent reports have shown that despite positive initial results with this approach, the majority of patients have loss of virologic control due to viral escape mutants.15 It is time for randomized, controlled trials of a variety of early treatment strategies in patients with primary HIV infection to help guide clinical management.

Copy right by HIV Institute Royal Organiztion 2005