John A. Bartlett

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AimTo estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. MethodsA systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. ResultsMedian log10 baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49 329 copies/ml) and 375 × 106 cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA ⩽ 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA ⩽ 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 × 106 cells/l (95% CI, 111 × 106 to 135 × 106 cells/l) and +160 × 106 cells/l (95% CI, 146 × 106 to 175 × 106 cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA ⩽ 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA ⩽ 50 copies/ml at week 48 (P = 0.0085). ConclusionsThe results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Addressing the challenges of adherence.

Summary: Adherence to antiretroviral therapy is a crucial determinant of treatment success. Studies have unequivocally demonstrated the close association between adherence and plasma HIV RNA levels, CD4 cell counts, and mortality in patients with HIV infection and disease. Adherence levels of ≥95% are required to maintain virologic suppression. However, actual adherence rates are often far lower; most studies show that 40% to 60% of patients are <90% adherent. Adherence also tends to decrease over time. Patients offer a range of reasons for nonadherence, but the most frequently cited one is simply that they forget; other reasons include being away from home, being busy, or experiencing a change in daily routine. Additional barriers to adherence include psychiatric disorders, such as depression or substance use, uncertainty about the effectiveness of treatment and the consequences of poor adherence, regimen complexity, and treatment side effects. Several strategies can be employed in the effort to support patients’ adherence, and all members of the multidisciplinary team should ideally employ these strategies in combination. Efforts should be made to educate and motivate patients, simplify treatment regimens and tailor them to individual lifestyles, prepare for and manage side effects, and address the concrete issues that may be a barrier to adherence. Recruiting an adherence monitor, providing memory aids to medication taking, and anticipating course corrections can also help patients achieve the adherence rates needed for successful treatment of HIV infection and disease.

Infectious Gastroenteritis in Bone-Marrow-Transplant Recipients

We prospectively evaluated infections with several gastrointestinal pathogens in patients undergoing bone-marrow transplantation, in an attempt to correlate infection with morbidity and mortality. Thirty-one of 78 patients (40 per cent) were infected with one or more of the following enteric pathogens during the study: adenovirus (12 infections), rotavirus (nine), coxsackievirus (four), or Clostridium difficile (12). Several patients were infected with more than one pathogen. Infection correlated with the occurrence of diarrhea and abdominal cramps. The mortality rate among the infected patients was 55 per cent--significantly higher than the rate (13 per cent) among the noninfected patients (P less than 0.001). This study indicates that enteric pathogens that often cause mild diarrhea in normal populations can cause serious infections in marrow-transplant recipients. Measures aimed at preventing or treating such infections might reduce the morbidity and mortality associated with marrow transplantation.

Severe Hepatotoxicity Associated with Nevirapine Use in HIV-Infected Subjects

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI) <18.5, female sex, serum albumin level <35 g/L, mean corpuscular volume >85 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection

Immunohistological analysis of the thymus in HIV infection. (a–d) Thymus from HIV-1+ patient no. 1 with no thymopoiesis. (e–h) Thymus from HIV-1+ patient no. 2 with areas of active thymopoiesis. (a) Hematoxylin and eosin stain of patient no. 1’s lymphoid thymus. ×13. (b) A similar area as in a, with thymic epithelium in immunohistological analysis reactive with antikeratin antibody (brown central areas). All keratin+ thymic epithelium (e) in the true thymus is collapsed (dark brown areas) and devoid of lymphocytes, with a surrounding infiltrate of blue mononuclear cells present in the thymic perivascular space (P). ×13. (c) Immunohistological stain of CD8+ T cells (brown cells; see arrows for examples) in the perivascular space (P) around a central empty thymic epithelial island (e). The dotted line surrounds thymic true epithelial thymus areas (e), and the short arrow points out a rare CD8+ T cell within the true epithelial thymus (e). ×66. (d) Many of the perivascular space (P) CD8+ cells are reactive with MAB TIA-1 (arrows) and therefore are mature effector cytotoxic T cells. ×66. e–h are from patient no. 2’s thymus. ×33. (e) Light microscopic view of patient no. 2’s thymus (hematoxylin and eosin stain with a Hassall’s body [h] in the thymus medulla). (f) Immunohistological analysis with antikeratin antibody, with areas of normal-appearing keratin+ thymic epithelium (brown areas) filled with lymphocytes (blue areas) intermingled with thymic epithelium (arrows). Most developing thymocytes are CD3+ T cells (arrows in g), many of which are normal CD1a+ cortical thymocytes (brown cells, arrows in h). A subset of these CD1a+, CD3+ immature thymocytes were actively dividing as determined by nuclear reactivity with MAB mib-1 (not shown). MAB, monoclonal antibody.

Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects

The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4+ T cells >400 per μl. CD4+ T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-γ-producing HIV-1-specific CD8+ and CD4+ T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8+ T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4+ T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4+ T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4+ T cell counts, and showed no enhancement of antiviral CD8+ T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study

Introduction The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. Methods and Findings We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Conclusions Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts.

Predictors of Incomplete Adherence, Virologic Failure, and Antiviral Drug Resistance among HIV-Infected Adults Receiving Antiretroviral Therapy in Tanzania

BACKGROUND Access to antiretroviral therapy is rapidly expanding in sub-Saharan Africa. Identifying the predictors of incomplete adherence, virologic failure, and antiviral drug resistance is essential to achieving long-term success. METHODS A total of 150 subjects who had received antiretroviral therapy for at least 6 months completed a structured questionnaire and adherence assessment, and plasma human immunodeficiency virus (HIV) RNA levels were measured. Virologic failure was defined as an HIV RNA level >400 copies/mL; for patients with an HIV RNA level >1000 copies/mL, genotypic antiviral drug resistance testing was performed. Predictors were analyzed using bivariable and multivariable logistic regression models. RESULTS A total of 23 (16%) of 150 subjects reported incomplete adherence. Sacrificing health care for other necessities (adjusted odds ratio [AOR], 19.8; P<.01) and the proportion of months receiving self-funded treatment (AOR, 23.5; P=.04) were associated with incomplete adherence. Virologic failure was identified in 48 (32%) of 150 subjects and was associated with incomplete adherence (AOR, 3.6; P=.03) and the proportion of months receiving self-funded antiretroviral therapy (AOR, 13.0; P=.02). Disclosure of HIV infection status to family members or others was protective against virologic failure (AOR, 0.10; P=.04). CONCLUSIONS Self-funded treatment was associated with incomplete adherence and virologic failure, and disclosure of HIV infection status was protective against virologic failure. Efforts to provide free antiretroviral therapy and to promote social coping may enhance adherence and reduce rates of virologic failure.

Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1.

Yeast strains isolated from the oropharynx of 87 consecutive patients infected with human immunodeficiency virus type 1 were examined for in vitro susceptibility to fluconazole. Candida albicans was isolated from 73 patients. Fifty-one patients had received antifungal therapy in the month preceding the yeast infection. Thirty-two patients had symptomatic oropharyngeal candidiasis. The MICs were correlated with azole use and with clinical symptoms and signs. Although there is overlap between groups, in vitro testing identified a large group of patients for whose yeast isolates the fluconazole MICs were high and who remained symptomatic while receiving azole therapy. This study supports the ability of in vitro testing to predict the clinical outcome of mucosal fungal infections. The study also demonstrates that azole resistance of oropharyngeal yeasts is a common problem in patients infected with human immunodeficiency virus type 1 and that this azole resistance has clinical relevance.

Pharmacogenetics of Nevirapine-Associated Hepatotoxicity: An Adult AIDS Clinical Trials Group Collaboration

Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C-->T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.30; P=.016).