Important note: Information in this article was accurate in May 2001. The state of the art may have changed since the publication date.
The 8th Conference on Retroviruses and Opportunistic Infections (8th CROI) had the expected wealth of papers dealing with adverse reactions to antiretroviral agents. Many of the papers had been presented previously or were extensions of studies previously reported. Unfortunately, there were no new data on pathophysiology and no breakthroughs in management.
Andrew Carr [State-of-the-Art presentation, Session 64] presented a review of lactic acidosis and some recommendations regarding management. The presumed mechanism is mitochondrial toxicity, and the drugs most frequently implicated are d4T, ddI, and AZT. The most common clinical manifestations are fatigue, weight loss, abdominal pain, liver disease, and lipoatrophy. The consequences may be particularly important in pregnancy, and the FDA has issued a warning regarding the use of d4T and ddI in pregnancy because of two lethal cases of lactic acidosis in pregnant women who received this combination. Dr. Carr did not recommend routine measurement of lactic acid levels. A venous lactate exceeding 2 mmol is abnormal; levels of 2-5 mmol are often asymptomatic; levels of 5-10 mmol are usually associated with symptoms; levels >10 mmol are always associated with symptoms, always show acidosis with pH <7.35, and have a mortality rate of nearly 80%. The frequency of lactic acidemia using the 2 mmol threshold is 2.1/1,000 patient-years; for moderate or severe lactic acidosis, the frequency is 0.013-0.8/1,000 patient-years. Carr recommended discon-tinuation of NRTIs for any level exceeding 10 mmol, and for levels of 5-10 mmol with symptoms that are not otherwise explained. Discontinuation should be considered in patients with levels of 2-5 mmol who have symptoms that are felt to be due to elevated lactate.
Lonergran and colleagues [Abstract 624] used the following case definition for lactic acidosis: An adult receiving an NRTI-containing regimen with hyperlactatemia accompanied by gastrointestinal complaints or otherwise unexplained elevated ALT. Using this definition, they report an incidence rate of 14.5/1,000 person-years among NRTI recipients. There were 33 cases, including 29 with gastrointestinal symptoms and 29 with elevated ALT. The median venous lactate level was 4.3 mmol/L. The incidence rates per 1,000 patient-years were as follows: d4T/ddI-58, d4T-26, d4T/ ABC-24, and AZT/3TC- 1.6. The authors reported that rechallenge with AZT, ABC, or both, were safe. When therapy with NRTIs was discontinued, the median time to normalization of lactic acid levels was 50 days.
Data from a number of studies presented in Chicago suggested that osteopenia and osteoporosis occur with increased frequency among HIV-infected individuals, but are not complications of antiretroviral therapy. Osteonecrosis, which can lead to avascular necrosis of the hips, is felt to be a separate entity, but the roles of HIV and antiretroviral therapy are also unclear. Investigators from Johns Hopkins reviewed the experience at the Johns Hopkins HIV Clinic from 1995 through 2000 and identified 15 cases of avascular necrosis for an incidence rate of 2.5/1,000 patient-years [Keruly, Abstract 637]. This greatly exceeds the rate of 0.04/1000 patient-years in the general population. The incidence of avascular necrosis increased steadily during the study period. The most frequently associated risk factors were steroid use in 34% and a CD4 count of <200/mm3 in 60%. Perhaps most significantly, over half of the patients had never received a PI or an NNRTI.
Because PI-based regimens are assumed to be responsible for insulin resistance, hyperlipidemia, and fat accumulation there is a great deal of interest in strategies involving switches from PI- to non-PI based regimens. One study showed that a change from a PI-containing regimen to efavirenz had no effect on insulin resistance [Estrada, Abstract 671], while in another study a change to abacavir was associated with improved glucose metabolism [Walli, Abstract 672]. Casado and colleagues reported the results of the BEGIN study in which patients with good virologic control but experiencing intolerance or toxicity on PI-containing regimens were changed to nevirapine or efavirenz [Abstract 673]. Switch to an NNRTI-based regimen was associated with a significant decrease in cholesterol (mean of 241 to 206 mg/dL) and triglyceride levels (mean of 286 to 194 mg/dL). Neither study demonstrated a substantial impact on lipodystrophy.
Structured Treatment Interruption (STI)
This widely used term actually encompasses three different strategies: 1) intermittent treatment designed to reduce cost and toxicity of HAART; 2) the temporary "drug holiday" to allow return of sensitive wild-type virus and relieve toxicity prior to reinitiating HAART, and 3) STI to permit regeneration of immune defenses against HIV.
There are two NIH protocols dealing with intermittent HAART. One is a pilot study reported by Dybul [Abstract 354], in which 12 patients with viral loads <500 c/mL for over six months on HAART took d4T, 3TC, IDV/RTV for cycles of seven days on followed by seven days off. Results were reported for the nine patients who continued the study through 24 weeks: All nine have maintained viral suppression. There was no important change in the CD4 cell count, and no resistance has been noted in isolates from lymph nodes or CD4 cell reservoirs. The other "intermittent" regimen from the NIH was also reported by Dybul [Abstract 364]. These patients had the same entry criteria, but were randomized to receive either continuous HAART or cycles of HAART with four weeks off and eight weeks on. Results were reported for 14 patients who underwent 2-5 cycles. These patients had viral rebound during their month off, but regained suppression with <50 c/mL with retreatment; there were slight decreases in the CD4 cell counts that were not significantly different from controls. These studies suggest that it may be possible to treat patients with intermittent cycles of HAART to reduce cost and toxicity, but the long-term safety and optimal dosing schedule have not been determined.
The largest study of STI in chronically infected patients was the Swiss-Spanish Intermittent Treatment Trial (SSITT), which was reported by Fagard [Abstract 357]. This is a relatively complicated protocol in which patients with a VL <50 c/mL for over six months and a CD4 count over 300 cells/mm3 at baseline were randomized either to receive continuous therapy or STIs with 8 weeks on therapy followed by two weeks off, for four cycles. At week 40, treatment was discontinued unless the VL rebounded to over 5,000 c/mL. In results reported for the 52-week data, 21 of 99 (21%) participants had a viral load that remained below 5,000 c/mL at 12 weeks without therapy. Thirty participants were excluded because their viral load exceeded 50 c/mL during the period on treatment. Thus, the number who responded is 21 of 129 (16%). No patient with a viral load >60,000 c/mL prior to beginning the initial HAART regimen achieved virologic control at 52 weeks. Failure to rebound in the first two cycles predicted long-term response. The authors seemed more enthusiastic about these results than did the audience.
Bruce Walker updated his experience with STI in patients treated during the acute retroviral syndrome [Abstract 294]. His cohort included 14 participants with an average HAART duration of 547 days. Of these, six have achieved durable control as defined by a viral load of <5,000 c/mL, four after a single interruption, and two after two interruptions. The period of virologic control off therapy has ranged from 80 to 450 days. His conclusion is that STI is a viable option in patients who are treated during the acute retroviral syndrome, due to a strong helper cell response and a relatively homogeneous viral population. This is in contrast to STI in patients with chronic infection, who have much greater viral diversity, and who have lost their HIV-specific immunity.
Treatment interruption prior to salvage therapy in patients who have failed HAART was addressed by Deeks and colleagues [Abstract 292]. Twenty-two patients with viral loads exceeding 2,500 c/mL while receiving a PI-based regimen discontinued treatment. Most had high levels of PI resistance. During a median treatment interruption of 18 weeks, there was a median decrease in CD4 cell count of 95/mm3 and a median increase in viral load of 0.74 log10 c/mL. Resistance studies showed that 18 of the 22 had a shift to increased PI-sensitivity, and 16 had improved susceptibility to NRTIs. The patients were retreated based on the new susceptibility profiles, and 11 of the 22 achieved VL <50 c/mL at 24 weeks on the new regimen. Some of the participants had re-emergence of resistant virus during salvage. The authors concluded that this form of treatment interruption may play a role, but the strategy is most likely to be successful if the salvage regimen includes a drug from a new class of agents.
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