A randomised control trial of structured interrupted generic antiretroviral therapy versus continuous therapy in HIV-infected individuals in Southern India.

This randomised control trial, conducted in Chennai, India, compared structured interrupted therapy (SIT) and continuous therapy (CT) in relation to immunologic and virologic outcomes, adverse events (AEs) and cost of therapy. ART-naïve adult HIV1-infected participants with CD4 counts 50-350 cells/mm(3), and plasma viral load (PVL)>5000 copies/mL were enrolled and placed on Indian-manufactured generic ART: zidovudine(AZT)/stavudine(d4T)+lamivudine(3TC)+efavirenz(EFV). After at least six months of continuous therapy, subjects were randomised to SIT (one-week-on/one-week-off cycles) or CT. The primary end-point was the proportion of subjects maintaining CD4>200 cells/mm(3) at six and 12 months after randomisation. Secondary end-points were effective viral suppression (PVL<400 copies/mL), AEs and cost. All analyses used intention-to-treat methodology. Of 40 participants (69% male; mean age 36+/-7; median baseline CD4 and PVL: 162 cell/mm(3)and 259,000 copies/mL), 17 were randomised to SIT and 18 to CT. At randomisation, median CD4s for SIT and CT were 378 cells/mm(3) and 357 cells/mm(3), respectively. All participants had PVL<400 copies/mL at time of randomisation. Median CD4 six months after randomisation was 498 cells/mm(3) and 417 cells/mm(3) for SIT and CT respectively. All participants had CD4>200 cells/mm(3). One participant on CT and two on SIT had sustained PVL>400 copies/mL. There were no serious AEs or deaths. Structured interrupted therapy cost was half of CT. Structured interrupted therapy was effective at maintaining CD4 above 200 cells/mm(3). Adverse events were comparable in both groups, with 50% reduction in cost for SIT. Further research on such strategies may benefit resource-constrained settings.

HIV in couples in South India; implications for prevention.

We studied HIV prevalence in couples in Chennai, India. In 56% both partners were infected. Among discordant couples, 35 men and seven women were infected. Heterosexual intercourse is the primary risk factor. Concordance was related to sex with commercial sex workers for men and to genital ulcer disease for women. Median CD4 count was 97 cells/mm(3) among concordant men, 222 cells/mm(3) among discordant men. Condom use increased, and frequency of sexual intercourse decreased, among all couples after HIV diagnosis.

Cancer incidence in women with or at risk for HIV.

The purpose of our study was to identify the types and rates of cancers seen in high-risk human immunodeficiency virus (HIV)-infected and HIV-uninfected women. From 1993 to 1995, 1,310 women enrolled at four urban U.S. research sites in the HIV Epidemiology Research Study and were interviewed biannually to identify interval diagnoses and hospitalizations until study closure in March 2000. Cancer incidence data were collected through abstraction of medical records and death certificates. Of 871 HIV-infected and 439 HIV-uninfected women, 85% had a history of smoking and 50% a history of injection drug use. For our analysis, 4,180 person-years were contributed by HIV-infected women, and 2,308 person-years by HIV-uninfected women. HIV-infected women had 8 non-Hodgkin's lymphomas, 5 invasive cervical cancers (ICC), 1 Kaposi's sarcoma and 12 non-AIDS defining cancers, including 4 lung cancers, compared with 4 cancers in HIV-uninfected women including 1 lung cancer (all cancers, 6.22/1000 person-years vs. 1.73/1000 person-years, p = 0.01). CD4+ cell counts were above 200/mm3 in all women with ICC. HIV-infected women with lung cancer were young smokers (mean age, 40 years), and all died within 6 months of diagnosis. Lung cancer occurred at twice the rate in HIV-infected vs. uninfected women in the cohort and severalfold above expected in age- and race-matched women in U.S. national data (incidence relative risk 6.39; 95% confidence interval 3.71, 11.02; p < 10(-7)). The frequent occurrence of cervical and lung cancers have important implications for the counseling (cigarette cessation), screening (PAP smears) and care of women with HIV infection, as they live longer because of current antiretroviral therapies.

A longitudinal analysis of hospitalization and emergency department use among human immunodeficiency virus-infected women reporting protease inhibitor use.

The impact of protease inhibitors (PIs) on emergency department (i.e., emergency room [ER]) visits and hospitalizations was examined among a cohort of human immunodeficiency virus (HIV)-infected and high-risk women followed-up in the HIV Epidemiology Research Study (HERS) from 1993 through 1999. The rates of hospitalization and ER visits were measured as a function of recent or current PI use, age, race, transmission risk category, HERS site, baseline CD4 cell count, and baseline virus load; the PI effect was estimated separately by baseline CD4 cell count. In the HERS, PI use was strongly associated with lower rates of ER visits and hospitalizations for patients with baseline CD4 cell counts of <200 cells/mL (for hospitalizations: rate ratio [RR], 0.54; 95% confidence interval [CI], 0.33-0.89; for ER visits: RR, 0.38; 95% CI, 0.24-0.61). Other factors associated with increased hospitalization and ER use included history of injection drug use, low CD4 cell counts, and high virus loads.

Plateau in body habitus changes and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy: a 3.5-year study.

BACKGROUND: In a previously reported study, 21 women (propositi) who reported changes in body habitus during highly active antiretroviral therapy (HAART) were evaluated and compared with 21 women (comparison group) on HAART who did not report body habitus changes. Mean durations of HAART at baseline evaluation were 12.5 and 15.2 months for the propositi and comparison group, respectively. OBJECTIVE: Follow-up of the propositi and comparison group was conducted to determine whether body habitus changes and lipid abnormalities are progressive, stable, or improved with time and alteration of the HAART regimen. METHODS: Patients were evaluated by standardized interview, physical examination, body weight, body mass index, CD4 cell count, plasma HIV RNA levels, and lipid profiles. RESULTS: Fourteen of 21 propositi were available for follow-up. The mean duration of HAART was 42.7 months; body habitus changes were stable in 10 of the 14 women. Thirteen of 21 women in the comparison group were available for follow-up after a mean duration of HAART of 38.5 months; 2 of the 13 women had developed body habitus changes at follow-up. In both groups, mean serum lipid values at follow-up remained elevated to levels associated with increased cardiovascular risk. CONCLUSIONS: Body habitus changes in women most often developed within 1 year of initiation of HAART. Changes were largely stable after 2.5 additional years of HAART. Only modest and inconsistent improvement was achieved with alteration in the HAART regimen. Serum lipid abnormalities evident within the first year of HAART were also stable with 2.5 additional years of therapy.

Association between bacterial vaginosis and expression of human immunodeficiency virus type 1 RNA in the female genital tract.

We assessed the effect of lower genital tract infections on human immunodeficiency virus type 1 (HIV-1) RNA shedding in the female genital tract. Bacterial vaginosis was significantly associated with HIV-1 RNA expression in the female genital tract of HIV-infected women.

Factitious HIV syndrome in young women.

Factitious HIV infection has been observed at our center in women presenting with a false history of HIV/AIDS. In a 2-year period, 4 women presented for HIV-related care, indicating they were HIV-seropositive, while repeated serologic testing revealed no evidence of HIV infection. In all cases, the women were either quite angry or appeared surprised when told that they did not have HIV infection. A common denominator in all 4 women was a history of prolonged sexual, physical, or emotional abuse. Three of the 4 had been to other physicians, changing doctors as soon as the absence of HIV infection was established. Appropriate psychiatric support is an important aspect in care of these women, although it may not be accepted. All presentations of HIV infection should be confirmed either by identifying hard-copy data of HIV test results or by retesting all patients before evaluation and treatment of presumed HIV-related illnesses.

Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women.

OBJECTIVE: To determine whether highly active retroviral therapy (HAART) is associated with better neurocognitive outcome over time among HIV-infected women with severely impaired immune function. METHODS: A semiannual neurocognitive examination on four tasks was administered: Color Trail Making, Controlled Oral Word Association, Grooved Pegboard and Four-Word Learning. This protocol was initiated in the HIV Epidemiological Research study (HERS) study when a woman's CD4 cell count fell to < 100 x 10(6) cells/l. Immune function (CD4), viral load status and depression severity (CESD) were also assessed semi-annually, along with an interview to determine medication intake and illicit drug use. RESULTS: HAART was not available to any participant at the time of enrollment (baseline), while 44% reported taking HAART at their most recent visit (mean duration of HAART 36.3 +/- 12.6 months). HAART-treated women had improved neurocognitive performance compared with those not treated with HAART. Women taking HAART for 18 months or more showed the strongest neurocognitive performance with improved verbal fluency, psychomotor and executive functions. These functions worsened among women not taking HAART. Substance abuse status, severity of depressive symptoms, age and educational level did not influence the HAART treatment effects on neurocognitive performance. Neurocognitive improvements were strongly associated with the magnitude of CD4 cell count increases. CONCLUSIONS: HAART appeared to produce beneficial effect on neurocognitive functioning in HIV-infected women with severely impaired immune systems. Benefits were greatest for women who reported receiving HAART for more than 18 months.

Quantification of HIV-1-specific T-cell responses at the mucosal cervicovaginal surface.

OBJECTIVE: To characterize HIV-1 specific cellular immune responses at mucosal surfaces using a rapid, sensitive enzyme-linked immuno-spot (ELISPOT) technique. DESIGN: Cervicovaginal mononuclear cells obtained from cytobrush and cervicovaginal lavage were assessed for production of interferon-gamma (IFN-gamma) in response to stimulation by HIV-1 antigens. HIV-1 specific responses were compared in a cross-sectional study of two HIV-1-positive patient groups: women not currently on antiretroviral therapy with peripheral CD4 cell counts > 250 x 10(6)/l (n = 12); and women on highly active antiretroviral therapy (HAART) (n = 9). METHODS: Mononuclear cells from peripheral blood or cervicovaginal specimens were assessed in an ELISPOT assay for responses to HIV-1 antigens expressed by recombinant vaccinia viruses. This assay detects primarily CD8 T cells and shows good correlation with MHC class I tetramer staining of cytotoxic T lymphocytes. RESULTS: HIV-1 specific IFN-gamma spot-forming cells were detected in cervicovaginal samples of one out of nine women (11%) on HAART and five out of 12 women (42%) not currently on HAART. In peripheral blood mononuclear cells, HIV-1 specific IFN-gamma spot-forming cells were significantly more numerous in women not currently on HAART than in women on HAART (P = 0.009). In most cases, antigens recognized by mucosal T cells were also recognized by PBMC; however, there were exceptions. CONCLUSIONS: HIV-1-specific antigen-reactive T cells may be detected in routine, noninvasive gynecological specimens. The results suggest that cervicovaginal HIV-1-specific T cells may be less numerous in individuals on HAART than in those not on HAART, as shown previously for HIV-1-specific cytotoxic T lymphocytes in the peripheral blood.

Neurocognitive and psychological contributions to quality of life in HIV-1-infected women.

OBJECTIVES: The purpose of this study was to examine the impact of neurocognitive and emotional distress and immune system dysfunction on quality of life in women with HIV. METHODS: Thirty-six HIV-seropositive women were administered measures of mood status (Profile of Mood States), quality of life (Multidimensional Quality of Life Questionnaire for Persons with HIV) and cognitive function. CD4 cell counts were obtained as an indicator of immune system status. RESULTS: Regression analyses revealed that independent of severity of emotional distress, neurocognitive deficits on measures of executive control and speed of information processing were associated with reduced quality of life. Emotional status also was associated with quality of life and together with neurocognitive performance accounted for most of the variance associated with quality of life. Reduced CD4 cell count was significantly associated with neurocognitive deficits, but not severity of emotional distress or quality of life. CONCLUSIONS: Quality of life among women who are infected with HIV is strongly influenced by both neurocognitive and emotional status, as women with the greatest neurocognitive impairment and emotional distress report the poorest quality of life.

Hit HIV-1 hard, but only when necessary.

Randomised, controlled trial data show that combination antiretroviral therapy for HIV-1 infection benefits people with CD4-cell counts less than 350 cells/microL. Based on currently known risks and benefits, we believe that if CD4-cell counts and viral load are monitored carefully, and highly active antiretroviral therapy (HAART) is started commonly when the CD4-cell count drops below 350 cells/microL, then clinically relevant immune-system damage and progression to AIDS and death can be greatly delayed or prevented. This approach is dictated by three features of HIV-1 infection that are not typical of infectious diseases: no available regimen can eradicate HIV-1; all currently effective regimens may cause undesirable, sometimes life-threatening, toxic effects; and, unless regimens are strictly adhered to, multidrug resistance can develop, limiting future treatment options. If therapy is started too early, cumulative side-effects of the drugs used and the development of multidrug resistance may outweigh the net benefits of the lengthening of life. If therapy is started too late, increases in disease progression and mortality outweigh the risk of adverse events. A patients' activist (MH) and a clinician (CCJC) discuss data that justify this balanced approach and the feasibility of randomised controlled trials to provide clearer answers about when to start treatment.

Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA.

OBJECTIVES: To determine the frequency of cervicovaginal lavage and plasma HIV-1 RNA levels that are below detectable levels (< 400 copies/ml) among women on highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in the blood plasma and genital tract among antiretroviral-naïve women. METHODS: Data were obtained from 205 HIV-infected women with paired plasma and cervicovaginal lavage viral load measurements. Seven antiretroviral-naïve women starting HAART had viral load measurements performed daily for one week, at 2 weeks and at 1 month after initiating therapy. Viral load quantification was carried out by nucleic acid sequence-based amplification assay. The lower limit of detection was 400 copies/ml. RESULTS: Plasma and cervicovaginal HIV-1 RNA was detectable in 71 and 26% of the women, respectively. Among women with plasma viral loads less than 400, 400-9999, and 10,000 copies/ml or over, genital tract HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per cent of the women with CD4 cell counts of less than 200/mm3 had detectable cervicovaginal viral loads compared with 18% among women with CD4 cell counts of 200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no therapy (P < 0.045). In seven antiretroviral-naïve women initiating HAART, cervicovaginal HIV-1 RNA decreased by 0.7-2.1 log10 within 1-14 days of starting therapy. CONCLUSION: The cervicovaginal HIV-1 RNA level was positively correlated with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART was significantly associated with below-detectable levels of HIV-1 RNA in both plasma and the genital tract. HIV-1 RNA suppression in the genital tract may occur rapidly after initiating therapy.

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

The management of the clinical complications of antiretroviral therapy.

In clinical practice, combination antiretroviral therapy is frequently complicated by adverse reactions and drug-related toxicities. The incidence, presentation, differential diagnosis, and management of the most frequent and severe of these complications are discussed. The recently described spectrum of metabolic complications, including hyperlipidemia, fat redistribution, and lactic acidosis, are covered in detail. The management of nephrotoxicity, pancreatitis, bone marrow suppression, peripheral neuropathy, and hypersensitivity reactions related to antiretroviral therapy is also discussed.

Should women with human immunodeficiency virus be delivered by cesarean?

Vertical transmission of human immunodeficiency virus (HIV) accounts for most new pediatric cases in the United States. With the routine use of zidovudine in the antepartum, intrapartum, and postnatal periods, transmission of HIV from mother to infant has decreased significantly during the past 5 years. Most transmission occurs during labor and delivery, so the effect of mode of delivery recently has been investigated. Several studies support cesarean to further reduce infection in newborns. However, those studies are limited by lack of data on concomitant effects of viral load and effects of combined antiretroviral therapy. There also might be increased operative morbidity in this population. Therefore, we suggest caution in establishing cesarean as a standard for delivery of HIV-infected women.

Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART).

Twenty-one women (propositi) who expressed serious concerns about changes in body habitus during highly active antiretroviral therapy (HAART) were evaluated by thorough physical examination, anthropometric measurements, and serum lipid and endocrine assays. The same evaluations were carried out in a comparison group of 21 women who received HAART but did not complain of changes in habitus. No significant demographic differences were found between the propositi and the comparison group, nor were there significant differences in CD4 count or plasma viral load (PVL) between the two groups. Lipid analyses were also performed on plasma obtained prior to HAART from 12 of the women. The frequency of changes reported by the 21 propositi were increase in abdominal size (90%), increase in breast size (71%), weight gain of >5 kg (43%), peripheral fat wasting (43%), buttock fat wasting (38%) and development of cervicodorsal fat pad (19%). A subset of patients in the comparison group experienced increase in abdominal size (29%) and weight gain >5 kg (19%), but none experienced clinically detectable peripheral or buttock fat wasting, increased breast size, or development of cervicodorsal fat pads. Mean waist circumference, waist-to-hip ratios (WHR), body fat, and body mass index (BMI) were above the desirable range for women in both propositi and the comparison group. Levels of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol associated with increased cardiovascular risk were found in 48%, 62%, 45%, and 33%. respectively, of the propositi, with similar findings in the comparison group. Fasting insulin levels were elevated in 4 propositi and 6 of the comparison group; mean insulin levels were within the normal range for both groups. In the comparison of lipids for the subset of patients before and after HAART therapy, HAART was associated with significant increases in total cholesterol, apolipoprotein B, and HDL cholesterol. Changes in body habitus caused by redistribution of fat occur commonly in women receiving HAART. Serum lipid abnormalities also are common during HAART and appear to be as frequent in women who do not experience clinically apparent body fat redistribution as in those who do. The observed changes in body fat distribution and in serum lipid levels are alterations that have been strongly correlated with increased risk for cardiovascular disease. Therefore, an understanding of the basis of these phenomena, and the risks with which they may be associated in this population, will be important for therapeutic decision making in women with HIV disease.

Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series.

BACKGROUND: The availability of sensitive assays for plasma HIV viral load and the trend toward earlier and more aggressive treatment of HIV infection has led to the inappropriate use of these assays as primary tools for the diagnosis of acute HIV infection. OBJECTIVE: To describe limitations in the use of plasma viral load testing for the diagnosis of HIV infection. DESIGN: Case series. SETTING: Academic medical centers in Providence, Rhode Island, and Worcester, Massachusetts. PATIENTS: Three persons in whom HIV infection was falsely diagnosed by plasma viral load testing. MEASUREMENTS: Laboratory measures and clinical outcomes. RESULTS: Two cases of false-positive results obtained by using branched-chain DNA plasma viral load assays and one case of a false-positive result obtained by using reverse transcriptase-polymerase chain reaction plasma viral load assay are reported. All three plasma viral load tests yielded positive results with low values (1254 copies/mL, 1574 copies/mL, and 1300 copies/mL). Infection with HIV was initially diagnosed in all three patients, but each patient subsequently tested negative by HIV-1 enzyme-linked immunosorbent assay and repeated plasma viral load testing. CONCLUSION: Physicians should exercise caution when using plasma viral load assays to detect primary HIV infection, particularly when the pretest probability of infection is low.

Mucosal candidal colonization and candidiasis in women with or at risk for human immunodeficiency virus infection. HIV Epidemiology Research Study (HERS) Group.

The epidemiology of mucosal candidal colonization and candidiasis was studied in a multicenter cohort of 871 human immunodeficiency virus (HIV)-seropositive and 439 demographically and behaviorally similar HIV-seronegative women. Cross-sectional analyses at baseline revealed that oropharyngeal colonization with Candida species was more prevalent among seropositive women and among women reporting recent cigarette smoking and injection drug use. Oropharyngeal candidiasis was also more prevalent among seropositive women. Both oropharyngeal colonization and candidiasis were significantly associated with a lower median CD4 lymphocyte count among seropositive women. Vaginal candidal colonization was more prevalent among seropositive women and among those reporting recent injection drug use and current insulin or oral antihyperglycemic therapy. Vaginal candidiasis was equally likely to be diagnosed in seropositive and seronegative women and was not significantly related to recent sexual contact. Neither vaginal colonization nor candidiasis was significantly related to a lower median CD4 lymphocyte count among seropositive women. Baseline evaluation indicated differences in the epidemiology of oropharyngeal and vaginal candidal colonization and candidiasis in HIV-seropositive women and suggested possible variation in pathogenesis of candidal infection at these two mucosal sites.