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The increasing availability of effective antiretroviral treatment (ART) has dramatically extended life expectancy for those with HIV infection1. As a result, people are aging with HIV2, but data on this new phenomenon remains somewhat limited and opinions vary. Some experts contend, now that we are successful at suppressing HIV-1 RNA, that HIV research and health care resources should be exclusively dedicated to ensuring access to ART and developing an effective vaccine. They argue against spending limited resources on complex issues of aging with HIV since many of these issues have bedeviled aging researchers for decades. Some also suggest that routine care of virologically suppressed patients can be managed in more patient-centered and financially less expensive primary care settings3. Others take a different view, suggesting that the pathophysiologic processes and socioeconomic supports of aging are substantially altered among those with HIV and that these alterations offer unique opportunities for scientific discovery and improved clinical management. They suggest that aging with HIV is an untapped laboratory for discovery that offers unique insights into larger issues of aging. They point out that treatment strategies among those aging with HIV are only beginning to take shape, offering a unique opportunity to use evidence to inform care. Many clinicians also argue that enough unique and challenging aspects related to the ongoing management of HIV remain, suggesting a continuing role for the HIV specialist4.

Background Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype. Methods We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2–3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%–85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP). Results Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio. Conclusions Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight ofor = 60 kg or 240 mg/1,200 mg q.i.d. if weight of60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 ofor = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

Distal sensory peripheral neuropathy (DSPN) has been reported in 5 to 75% of patients with human immunodeficiency virus (HIV) infection, particularly in advanced stages of the disease. Twenty HIV seropositive patients were studied prospectively to determine the frequency of DSPN in clinical stage II and III of the HIV infection, and to investigate the role of vitamin B12 deficiency on the frequency of DSPN in HIV patients. All patients had complete blood count, serum vitamin B12 level, anti-intrinsic factor antibody, Schilling test, and electrodiagnostic studies including nerve conduction studies and concentric needle examination in the lower extremities, and sympathetic skin responses. Only 1 patient (5%) had clinical and electrophysiological evidence of possible DSPN. Of the 6 patients with abnormal Schilling test, only one had DSPN based on distal sensory symptoms, abnormal neurological examination and electrodiagnostic studies. Evidence for possible DSPN was present in 5% of patients with early HIV infection and did not appear to be more frequent in patients with concurrent vitamin B12 deficiency.

Background. Tesamorelin, a growth hormone‐releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%‐20% over 6‐12 months in individuals with human immunodeficiency virus (HIV)‐associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes. Methods. In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with $8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders. Results. Compared with tesamorelin nonresponders, responders experienced greater mean (6SD) reduction in triglyceride levels (26 weeks: 20.6 6 1.7 mmol/L vs 20.1 6 1.2 mmol/L [P 5 .005]; 52 weeks: 20.8 6 1.8 mmol/L vs 0.0 6 1.1 mmol/L [P 5 .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 6 16 mg/dL vs 5 6 14 mg/dL [P 5 .01]; 52 weeks: 21 6 14 mg/dL vs 8 6 17 mg/dL [P , .001]), hemoglobin A1c levels (26 weeks: 0.1 6 0.3% vs 0.3 6 0.4% [P , .001]; 52 weeks: 0.0 6 0.3% vs 0.2 6 0.5% [P 5 .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT. Conclusions. In contrast to nonresponders, HIV-infected patients receiving tesamorelin with $8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. Clinicaltrials.gov Registration. NCT00123253, NCT00435136, NCT00608023.

The use of antiretroviral therapies has improved survival in people living with HIV to nearly normal rates. However, ongoing low-level HIV replication and incomplete immune recovery are associated with a chronic inflammatory stimulus. This increases several non-typically AIDS-related complications, including fat mass changes and metabolic conditions. Abdominal adiposity occurs as a result of complex interactions involving HIV itself, antiretroviral drug–associated factors, and several intermediary metabolic alterations and abnormal hormone levels. Abdominal adiposity in turn can further the metabolic derangements, and increase the risk of diabetes and cardiovascular disease. Abnormal growth hormone secretion plays a role in development of the fat depot changes. Effective long-term interventions to decrease central adiposity are limited but studies using growth hormone and especially growth hormone–releasing factor have shown encouraging results. Other emerging therapeutic options have been variably successful in the short term and the continuing clinical and therapeutic challenges will require ongoing investigation.

In untreated HIV patients growth hormone deficiency contributes to loss of lean and fat mass. Pharmacologic doses of growth hormone successfully reverse this wasting process. In patients responding to antiretroviral therapies several non AIDS-related complications usually common among older, uninfected persons now occur more frequently in younger HIV patients. Among these conditions are cardiovascular disease and metabolic disorders. Although their etiology is multifactorial, changes in growth hormone biology reflecting relative growth hormone deficiency occur and may be involved. In these patients truncal obesity, and associated dyslipidemia and glucose homeostasis changes contribute to impaired quality of life and increased cardiovascular risk. Treatment with growth hormone and growth hormone releasing factor leads to short-term improvement of some of these abnormalities. This paper will review abnormalities of growth hormone biology and the use of growth hormone and growth hormone releasing factor as therapeutic agents in HIV patients.

OBJECTIVE To report the effects of tesamorelin, a growth hormone-releasing hormone analogue, on inflammatory and fibrinolytic markers and to relate these effects to changes in visceral adipose tissue (VAT). DESIGN AND METHODS Four hundred and ten HIV-infected patients with abdominal adiposity were randomized to 2 mg tesamorelin (n = 273) or placebo (n = 137) subcutaneously daily for 26 weeks. Circulating plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, C-reactive protein (CRP), and adiponectin were assessed. RESULTS At baseline, VAT was significantly associated with PAI-1 antigen (ρ = 0.36, P < 0.001), tPA antigen (ρ = 0.29, P < 0.001), CRP (ρ = 0.18, P < 0.001), and adiponectin (ρ = -0.22, P < 0.001). Treatment with tesamorelin resulted in a significant decrease from baseline in tPA antigen (-2.2 ± 2.5 vs. -1.6 ± 2.9 ng/ml, tesamorelin vs. placebo, P < 0.05). Changes in PAI-1 antigen were not significant in the tesamorelin group compared to placebo. Among patients receiving tesamorelin, changes in inflammatory markers were associated with change in VAT (PAI-1 antigen: ρ = 0.16, P = 0.02; tPA antigen: ρ = 0.16, P = 0.02; adiponectin: ρ = -0.27, P < 0.001), and these associations remained significant when controlling for changes in insulin-like growth factor-1. CONCLUSION In HIV patients with abdominal adiposity, tesamorelin may have a modest beneficial effect on adiponectin and fibrinolytic markers in association with changes in VAT. Further studies are needed to determine the clinical significance of these changes. These data further highlight the deleterious role of excessive VAT and the utility of strategies to improve VAT in this population.

HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT).Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat.Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension.A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197).Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily.We evaluated percent change in VAT by computed tomography scan at wk 26.At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52.Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH(1-44)) in HIV-infected patients with central fat accumulation.A 12-month study of 404 HIV-infected patients with excess abdominal fat in the context of antiretroviral therapy was conducted between January 2007 and October 2008. The study consisted of 2 sequential phases. In the primary efficacy phase (months 0-6), patients were randomly assigned to receive tesamorelin [2 mg subcutaneous (SC) every day] or placebo in a 2:1 ratio. In the extension phase (months 6-12), patients receiving tesamorelin were rerandomized to continue on tesamorelin (2 mg SC every day) or switch to placebo. Patients initially randomized to placebo switched to tesamorelin. Patients and investigators were blinded to treatment assignment throughout the study. The primary endpoint was visceral adipose tissue (VAT). Secondary endpoints included body image, IGF-I, safety measures, including glucose, and other body composition measures.VAT decreased by -10.9% (-21 cm(2)) in the tesamorelin group vs. -0.6% (-1 cm(2)) in the placebo group in the 6-month efficacy phase, P0.0001. Trunk fat (P0.001), waist circumference (P = 0.02), and waist-hip-ratio (P = 0.001) improved, with no change in limb or abdominal SC fat. Insulin-like growth factor-1 increased (P0.001), but no change in glucose parameters was observed. Patient rating of belly appearance distress (P = 0.02) and physician rating of belly profile (P = 0.02) were significantly improved in the tesamorelin vs. placebo-treated groups. The drug was well tolerated. VAT was reduced by approximately 18% (P0.001) in patients continuing tesamorelin for 12 months. The initial improvements over 6 months in VAT were rapidly lost in those switching from tesamorelin to placebo.Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose.

OBJECTIVE Treatment of HIV patients with daily tesamorelin, a growth hormone-releasing factor analogue, for 26 weeks resulted in a significant decrease in visceral adipose tissue (VAT) and improvement in lipids. The objective of the 26-week extension phase was to evaluate long-term safety and effects of tesamorelin. DESIGN HIV patients with central fat accumulation in the context of antiretroviral therapy were randomized to tesamorelin 2 mg (n = 273) or placebo (n = 137) s.c. daily for 26 weeks. At week 26, patients originally on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 154) or placebo (T-P group, n = 50), whereas patients originally on placebo were switched to tesamorelin (P-T group, n = 111). METHODS Safety included adverse events and glucose parameters. RESULTS Tesamorelin was generally well tolerated. The prevalence of adverse events and serious adverse events during the extension phase was comparable with the initial phase. Changes in glucose parameters over 52 weeks were not clinically significant and similar to those after 26 weeks. The change in VAT was sustained at -18% over 52 weeks of treatment (P < 0.001 versus baseline) as was the change in triglycerides (-51 mg/dl, P < 0.001 versus baseline). Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein decreased minimally over 52 weeks. Upon discontinuation of tesamorelin, VAT reaccumulated. CONCLUSION Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose. Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment.

Patients with human immunodeficiency virus (HIV) infection have sustained alterations in metabolism (lipids and insulin/glucose homeostasis) and body composition (fat distribution) that are proatherogenic (the Figure). HIV infection itself and/or its therapies may contribute to these alterations (the Table); although most effects are reversible, there are some possibly irreversible consequences of treatment. With the relative restoration to health seen in the era of highly active antiretroviral therapy (HAART), many traditional risk factors and promoters of dyslipidemia and diabetes also are present; they interact with HIV-specific inducers to worsen dyslipidemia and to increase the prevalence of insulin resistance and diabetes. Figure. Overview of the effects of HIV and its therapies on CVD risk. The contribution of traditional risk factors must be kept in mind, and they may occur with increased prevalence in people with HIV infection (eg, smoking). HIV, likely through the inflammatory response, and antiretroviral therapies independently affect many of the mediators of CVD risk. The effects on lipids are a prominent but complex example; HIV infection lowers LDL levels, but antiretroviral therapy raises LDL back up to normal levels. The bidirectional arrows indicate associations, but there is not yet adequate proof of causality. The dotted arrow between body composition and CVD indicates that body fat is known to affect the mediators such as dyslipidemia and insulin resistance but may also have a direct effect. FFA indicates free fatty acids; ARV, antiretroviral. View this table: Table. Effects of HIV Treatment These disturbances in lipid and glucose metabolism and renal disease may contribute, at least in part, to the excess cardiovascular disease (CVD) morbidity and mortality observed in HIV-infected individuals (the Figure). However, the relative contribution to excess CVD risk of traditional CVD risk factors, especially smoking, compared with these infection- and treatment-specific complications requires clarification. More prospective data with multivariable modeling are needed. …

Using a dual color ELISPOT assay able to detect HIV-specific IFN-gamma, IL-2 and dual IFN-gamma/IL-2 secreting lymphocytes we screened for HIV peptide-specific responses directed against the entire HIV proteome in two groups of untreated HIV-infected individuals, slow progressors (SP) and progressors. We found that the three functional lymphocyte subsets contributed differentially to individual HIV peptide-specific responses within a study subject. Among the identified stimulatory peptides, a higher proportion induced dual IFN-gamma/IL-2 secretion in SP than progressors. While the magnitude of single IFN-gamma secreting lymphocytes is similar between groups, the magnitude of peptide-specific dual IFN-gamma/IL-2 secreting lymphocytes is significantly more intense in SP. Neither single nor total IFN-gamma secreting cell magnitude and breadth measurements correlated with CD4 cell count or viral load whereas both parameters of dual IFN-gamma/IL-2 secreting responses correlated positively with CD4 counts and negatively with viremia.

Approximately two years after the introduction of highly active antiretroviral therapy for the treatment of HIV infection, body shape changes and metabolic abnormalities were increasingly observed. Initially, these were ascribed to protease inhibitors, but it is now clear that nucleoside reverse transcriptase inhibitors also contribute to lipodystrophy syndrome. The syndrome groups together clinical conditions describing changes in body fat distribution that include lipoatrophy, lipoaccumulation or both. However, there does not appear to be a direct link between lipoatrophy and lipoaccumulation that would support a single mechanism for the redistribution of body fat. Currently, there is no clear definition of lipodystrophy, which explains the difficulty in determining its prevalence and etiology. There are no current guidelines for the treatment of fat distribution abnormalities that occur in the absence of other metabolic complications. The present article reviews the current state of knowledge of the definition, symptoms, risk factors, pathogenesis, diagnosis and treatment of the morphological changes associated with lipodystrophy syndrome.

It is well established that body weight influences bone mass, but there is considerable controversy in the literature as to whether the principal determinant is lean mass, fat mass, or combinations of both, with variable degrees of relative influence as a function of age and sex. Total body and regional tissue composition studies were performed with DXA in a cohort of 102 HIV+ males who were on highly active antiretroviral therapy. These medications may be associated with a unique peripheral lipoatrophy without commensurate loss of lean tissue mass, and thereby provide an opportunity to assess the relative influence of fat mass on BMC levels in the absence of lean mass change. A comparison of the first quartile of peripheral fat (the lowest fat mass) with the remainder of the cohort showed no significant difference in lean mass in the total body, trunk, lower limbs, and upper limbs. In contrast, a significantly lower BMC was registered in the first peripheral fat quartile for all regions, implying an association of fat mass with BMC. By quartile stratification of the regional BMC, a comparison of the first and fourth quartiles demonstrated that the percentage fat mass decrease exceeded the lean mass decrease by a factor of 1.8 to 4.5. Regional BMCs were also stratified into two groups, ≤50 percentile and >50 percentile, and analyzed by Spearman correlation and robust multiple regression. It was found that lean mass was a determinant of BMC in both groups, whereas fat mass was an independent predictor in the >50 percentile BMC group only. The BMD t-score for the total hip was significantly lower in the first quartile of lower limb fat mass than the t-score of the remaining cohort, but this difference was not significant for the BMD lumbar spine t-score. This is a reflection of the influence of preferential local peripheral lipoatrophy on the adjacent mineral content and provides further evidence of fat mass as a determinant of BMC in addition to lean mass.

In recent years, a spectrum of metabolic and morphologic alterations has emerged among patients infected with human immunodeficiency virus (HIV) receiving antiretroviral treatment. Changes observed include insulin resistance, dyslipidemia, abdominal and dorsocervical fat accumulation, and fat depletion in the extremities and in the face. The health consequences of these changes are not well understood but may include increased risk for diabetes, heart disease, and stroke. Therefore, clinicians that treat patients with HIV need current, practical information on management strategies and interventions for patients with manifestations of HIV-associated lipodystrophy. Literature is reviewed on the health consequences of insulin resistance, dyslipidemia, and alterations in body fat distribution in non-HIV populations to gain perspective on how such abnormalities might affect HIV-infected patients. We also suggest treatments and strategies to manage metabolic and morphologic changes in patients with HIV.

Objectives: To determine the prevalence and describe the clinical correlates of subnormal cobalamin levels in subjects infected with the human immunodeficiency virus (HIV), and to assess its relationship to virus-mediated immunosuppression and/or anti-viral therapy. Setting: Outpatient referral clinic in tertiary care hospital. Patient population: 200 HIV infected individuals. Study design: Descriptive cross sectional survey, with prospective follow-up in a subgroup of patients before and after initiation of zidovudine therap. Measures: Routine complete blood count, serum B12 assay, CD4 counts. Serum homocysteine levels, and Schilling tests were performed on subgroups of study subjects. Results: Subnormal serum B12 levels were found in 61 subjects (30.5%). B12 deficient subjects were more likely to be taking zidovudine. (P = .007). Serum homocysteine levels were significantly higher in patients with subnormal cobalamin levels but were unrelated to CD4 counts or zidovudine use, and were rarely outside of the normal range. Malabsorption of vitamin B12 as evidenced by abnormal Schilling tests was more likely among patients with more advanced HIV disease, or gastrointestinal symptoms but was not necessarily associated with low B12 levels. Conclusions: Decreased cobalamin levels are found frequently in HIV disease, especially among those treated with zidovudine. Evidence of B12 malabsorption is found among those with more advanced disease and gastrointestinal symptoms.

Metabolic complications are common in treated HIV patients. Their etiology is multifactorial and the development of increased abdominal fat contributes to cardiovascular risk and impaired quality of life. Treated patients with fat mass distribution changes have relative growth hormone deficiency. Both pharmacologic and physiologic doses of growth hormone reduce the increased visceral adipose tissue and improve the associated abnormal lipid profiles in short-term studies. However, impaired glucose homeostasis changes and significant musculoskeletal toxicity occurs. A novel growth hormone-releasing factor analogue, tesamorelin, provides a physiologic means of restoring a normal growth hormone secretion profile and reduces increased visceral adipose tissue, improving both abnormal lipid profiles and patients' quality of life. Glucose homeostasis is generally well maintained. Cessation of treatment with either growth hormone or tesamorelin results in a prompt return of truncal obesity. Management strategies for the long-term maintenance of the reduced visceral adipose tissue have not yet been clarified and long-term effects on decreasing cardiovascular risks and improving clinical outcomes are uncertain.

Objective To assess the safety and efficacy of aerosol pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Participants Patients recovering from a first confirmed episode of AIDS-related P. carinii pneumonia who had no evidence of either another active AIDS-defining opportunistic infection or another pulmonary abnormality were considered eligible for the study but were included only if they had received no immunomodulators or antiretroviral agents other than zidovudine within 30 days of entry. One hundred sixty-two patients were randomized and started on the study drug. Intervention Patients were randomly assigned to receive aerosol pentamidine, 60 mg per dose, or placebo, delivered using a hand-held, patient-triggered, ultrasonic nebulizer. The induction phase of treatment consisted of 5 doses over 14 days, followed by a maintenance phase beginning on day 21 and consisting of one dose every 2 weeks. Results Thirty-two cases of P. carinii pneumonia were diagnosed before the termination of the trial; 27 cases occurred among 78 patients receiving placebo and 5 occurred among 84 patients receiving aerosol pentamidine. Estimates of the cumulative relapse rate of P. carinii pneumonia by 24 weeks were 50% and 9% for the placebo and pentamidine groups, respectively (P less than 0.001). Adverse reactions attributed to the study drug occurred in 15 of 78 patients receiving placebo and in 28 of 84 patients receiving pentamidine (P = 0.04). These were all mild or moderate in severity and did not preclude continued administration of the study drug. Conclusion Intermittent therapy with aerosol pentamidine is highly effective and well tolerated as secondary prophylaxis for AIDS-related P. carinii pneumonia.

To characterize the nature, time course and dose dependency of zidovudine-related side effects, we undertook a multicenter, prospective, dose-range finding study. Our study group consisted of 74 HIV-positive homosexual men belonging to groups II B, III and IV C2 from the Centers for Disease Control (CDC) classification of HIV disease. Following a 3-week observation period, volunteers were treated with zidovudine 600 mg/day for 18 weeks, 900 mg/day for 9 weeks and 1200 mg/day for 9 weeks, followed by a washout period of 6 weeks after which they were re-started on 1200 mg/day or the highest tolerated dose at 8-hourly intervals. Subjects were randomly assigned to 4-hourly or 8-hourly regimens within CDC groups while taking 600 and 1200 mg/day. Clinical and laboratory evaluations were performed at 3-week intervals. Symptomatic adverse effects were present in 96% of subjects, most commonly nausea (64%), fatigue (55%) and headache (49%). These were generally self-limited, reappearing briefly at each dose increment. A decrease in hemoglobin occurred shortly after initiation of therapy. This was not dose dependent and reversed rapidly upon discontinuation of treatment. A red blood cell count decrease, a mean cell volume increase and a granulocyte count decrease developed early in a dose-independent fashion, reverting at least partially during the washout phase. The decrease in reticulocyte count was dose related between 600 and 900 mg/day with no further change when the dose was escalated to 1200 mg/day. Bone marrow changes occurred rapidly as demonstrated by megaloblastosis in 95% of 65 specimens at week 18. We conclude that zidovudine-related hematological effects include a mild macrocytic megaloblastic anemia with a decrease in reticulocyte count and granulocytopenia. These effects are dose independent in the range 600–1200 mg/day and rapidly reversible upon discontinuation of the drug.

To the Editor. —We read with interest the letter by Fabris et al1reporting decreased levels of serum zinc in human immunodeficiency virus (HIV)-infected individuals. As part of an ongoing nutritional study of HIV disease, we have determined serum zinc levels in over 150 subjects classified according to current Centers for Disease Control criteria.2We concur with Fabris et al— serum zinc levels in subjects with group IV HIV disease were low (Figure), except for our group IV-C2patients, who had serum zinc levels similar to those of our controls. Contrary to the findings of Fabris et al, we did not find low levels of serum zinc in 35 subjects with generalized lymphadenopathy. Pifer et al3have suggested that lower zinc levels may be a life-style factor predisposing to further HIV-induced immunosuppression. As HIV serology was not assessed in their population of homosexual men without acquired

In Reply.— We concur with Shoemaker et al that the leukocyte zinc concentration may be an inadequate marker of zinc status in human immunodeficiency virus (HIV)—infected subjects. Zinc is important for normal cell-mediated immune function. Naturally occurring or experimentally induced zinc deficiency states lead to reversible immune abnormalities, including thymic atrophy, lymphopenia, reduced mitogen responsiveness, and impaired T-helper cell function. 1 Human immunodeficiency virus infection causes similar abnormalities. A recent report 2 suggested a possible role for zinc in the control of the HIV regulatory protein Tat (transactivator). A reliable measure of total body zinc concentration remains to be universally accepted by investigators, making the correlation between functionally significant zinc deficits and observed concentrations difficult. Zinc concentration may be determined in serum, erythrocytes, leukocytes, proteins, urine, hair, muscle, and bone, as well as several zinc metalloenzymes. 1 It is uncertain whether a fall in zinc concentration in a particular compartment

To the Editor.— A Canadian multicenter study, started in 1986, has assessed the potential toxic effect of zidovudine in 72 adults infected with human immunodeficiency virus (HIV)-1 (Centers for Disease Control stages II and III). Study. — Isolation of HIV-1 from circulating mononuclear cells of each subject was carried out both before the start of therapy and at regular intervals thereafter. Subjects received 600 mg/d of drug for 18 weeks, 900 mg/d for the subsequent nine weeks, and 1200 mg/d for a further nine-week period. After 36 weeks of therapy, subjects did not receive zidovudine for a six-week washout period designed to establish the reversibility of the hematologic effects of the drug. 1 Zidovudine therapy was then restarted at 42 weeks at a dose of 1200 mg/d. Human immunodeficiency virus was isolated successfully 2 in 33% and 41% of patients six weeks before and at the start of therapy, respectively.