Influence of Participant Perceptions of Adherence-Related Interactions with Study/Study Team on Drug Levels: HPTN069 Analysis of Self-Reported Adherence Experiences While on Study.

Adherence to HIV pre-exposure prophylaxis (PrEP) study drug is critical for safety, tolerability, and efficacy trials, and may be affected by how adherence is communicated by the study staff to trial participants. Increasingly, clinical trials investigating PrEP are creating and implementing 'participant-centered' approaches that discuss potential non-adherence neutrally (without negative judgement) and support efforts to adhere versus insisting on perfect adherence. In the HPTN069/ACTG A5305 study, we evaluated participant experiences of potentially negative adherence-related interactions with study teams using ten items to characterize the frequency of such experiences. We related these individual items and a combined set of seven negative experience items (total negative experience score) to drug concentrations (detectable or consistent with daily-dosing). The exploratory analyses used logistic regression for each experience item on the full sample and disaggregated by sex. Several experiences were related to drug detection and to daily-dosing, although more so for participants identifying as men than women. Total negative experience scores associated with not having detection drug concentrations for the full sample, and remained significant even when controlling for sex, age, and race. Daily dosing was associated with total negative experience score for men in the sample. Additional investigations into adherence-related interactions with study teams that are most problematic or helpful in general and uniquely for men and women are warranted.

Combination therapy for patients with HIV-1 infection: the use of dual nucleoside analogues with protease inhibitors and other agents.

This report reviews the design and preliminary results of ongoing and new studies that are evaluating novel antiretroviral drug combinations for the treatment of patients with HIV-1 infection. The studies reviewed in this report are: (1) Selection of Thymidine Analogue Regimen Therapy (START) I and II which compare three-drug combinations of stavudine (d4T), lamivudine (3TC), and indinavir, or d4T, didanosine (ddI), and indinavir versus zidovudine (ZDV), 3TC, and indinavir; (2) ATLANTIC, a study that compares d4T and didanosine (ddI) in combination with a third agent, either 3TC, nevirapine, or indinavir; and (3) the OZCOMBO studies: OZCOMBO 1, which compares two-drug combinations of d4T and 3TC, d4T and ddI, and ZDV and 3TC, all in combination with indinavir, and OZCOMBO 2, which compares two-drug combinations of d4T and ddI, ZDV and ddI, and ZDV and 3TC, all in combination with nevirapine. Preliminary results from these studies suggest that novel dual-nucleoside analogue reverse transcriptase inhibitor pairs, d4T and 3TC, d4T and ddI, and ZDV and ddI, as part of three-drug combinations, achieve antiretroviral effects comparable to ZDV- and 3TC-based three-drug combination regimens.

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I).

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884.

OBJECTIVE: To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DESIGN: Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SETTING: Multicenter study of the AIDS Clinical Trials Group (ACTG). PATIENTS: HIV-infected subjects. INTERVENTIONS: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. MAIN OUTCOME MEASURES: Area under the concentration-time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. RESULTS: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. CONCLUSIONS: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.

ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results.

OBJECTIVE: To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals. DESIGN: Prospective, randomized, double-blind, multicenter. METHODS: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68). RESULTS: Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 x 10(6)/l and 310 x 10(6)/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50-100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound. CONCLUSIONS: ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.

New antiretroviral drugs.

Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.

When to switch and what to switch to: strategic use of antiretroviral therapy.

Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.

Salvage therapy.

AIDS: The current guidelines for HIV therapy are two nucleoside analog reverse transcriptase inhibitors (NRTIs) in combination with one or two protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). These guidelines are based on clinical trials geared toward reducing viral loads to undetectable levels. In 10 to 20 percent of patients, however, such a reduction in viral load will not be accomplished. Virologic failure rates observed in cohort studies in the United States and Europe have reached rates as high as 60 percent after a year of treatment. Some predictors of treatment failure include higher viral load baselines, lower baseline CD4-cell counts, and failure to initiate treatment with an NNRTI. Clearly, better approaches to salvage therapy are needed. Studies include the evaluation of effectiveness of switching treatments from one PI to another, newer drugs, and multidrug regimens. Two tables, involving current guidelines for and major prospective studies on salvage therapy, are provided. In addition, the use of resistance testing in monitoring salvage therapy is discussed.^ieng

Pursuing a diagnosis in a Caribbean man.

AIDS: A case study of an HIV-infected Caribbean male with extrapulmonary tuberculosis details his diagnosis, treatment regimens, and follow-up. His presenting symptoms included epigastric pain and fever. Endoscopy and gastric biopsy showed gastritis and helicobacter infection, which were treated symptomatically, and TMP-SMX was given for possible salmonellosis. Serologic tests for common opportunistic infections were negative. After all other expected conditions were ruled out, concurrent symptoms were diagnosed as extrapulmonary tuberculosis, and multi-drug treatment was successfully conducted. The problem of interactions between protease inhibitors and anti-tuberculosis drugs in treating HIV and tuberculosis concurrently is discussed. Three options are addressed: (1) discontinue (or delay starting) the protease inhibitor until at least 6 months of a standard rifampin-containing tuberculosis regimen is completed; (2) discontinue (or delay starting) the protease inhibitor until 2 months of a standard rifampin-containing regimen are completed; and (3) use of rifabutin rather than rifampin.^ieng

Reappearance of a remotely acquired infection.

AIDS: A case is described of a profoundly immunosuppressed Brazilian man with AIDS presenting with a cough, abdominal and groin pain, shortness of breath, and wheezing. Past history included Pneumocystis pneumonia, and asthma that had been managed with bronchodilators. The patient also had a history of poor compliance with TMP-SMX prophylaxis. Prior to making a confirmed diagnosis, he is treated with antibacterial agents, TMP-SMX, and steroids. After results of a bronchoscopy and sigmoid oscopy showed adult strongyloides worms, the patient was treated with thiabendazole. Despite aggressive treatment, the patient died after a few days. This case indicates the need to screen for endemic organisms that can be reactivated in the immunocompromised host.^ieng

Abdominal pain in a man with HIV, TB, and KS.

AIDS: A case history is presented of a 29-year-old male diagnosed with tuberculosis, HIV, and Kaposi's sarcoma. Upon admission to the hospital for weight loss and diarrhea accompanied by acute pain in the abdomen, a battery of tests, including a CT scan, laboratory tests, and physical examination were performed. Results of the CT scan showed intestinal dilatation and nodular masses in the small bowel. Surgical evaluation and pathology determined intussusception secondary to Kaposi's sarcoma nodules.^ieng

FUO in a 56-year-old woman.

AIDS: A 56-year-old, obese woman who had been sexually inactive for 10 years presented at the hospital with high fevers, decreased appetite, nausea, vomiting, and weight loss. Following many diagnostic tests that revealed little, it was found that her estranged husband was being treated for Pneumocystis carinii pneumonia (PCP). The woman was tested for HIV and found to be positive. This is an example of the Centers for Disease Control and Prevention's (CDC) indication that 10 percent of reported AIDS cases occur in people over age 50, that diagnosis is often delayed in older age groups, and that anyone suffering from fever of an unknown origin should be tested for HIV. In such situations it is suggested that general practice include seeking behavioral information and offering HIV testing and counseling.^ieng

Too little of a good thing.

AIDS: A case study is presented on the therapeutic dilemmas surrounding the introduction of antiretroviral therapy. Such dilemmas can include a patient's willingness to understand and adhere to a prescribed regimen or how to deal with side effects that may occur as a result of a regimen. This case involves a 38-year-old, HIV-positive male who, in response to numbness in his left foot, reduced his dosage of d4T by half, without consulting his physician. Now that the numbness has disappeared, the patient opposes returning to the original dosage of d4T. Opinions on this case are provided by two medical professionals, along with their suggestions for accommodating the patient.^ieng

Current antiretroviral therapy: an overview.

Advances in the understanding of human immunodeficiency virus (HIV) pathogenesis, clinical assessment with viral load testing and the availability of potent combination antiretroviral therapy regimens have led to significant changes in options for HIV-infected patients. From the first approved antiretroviral agent, zidovudine (AZT), through two-drug nucleoside analogue regimens, to the current three-drug combination regimens with protease inhibitors, both the benefits of therapy and the complexities of therapy continue to increase. With the clinical benefits come associated lifestyle constraints and, thus, the impact and assessment of potent antiretroviral therapy on patient quality of life (QoL) becomes increasingly complicated.

Dextran sulfate and heparin interact with CD4 molecules to inhibit the binding of coat protein (gp120) of HIV.

Dextran sulfate, heparin, and certain other sulfated polysaccharides potently inhibit the adsorption of HIV to CD4+ cells. The mechanism of this inhibition is unclear and, specifically, it is unknown if these agents act at the level of CD4-gp120 binding. For example, previous reports have demonstrated that dextran sulfate does not inhibit the cell surface binding of anti-CD4 mAb known to be directed at the gp120 binding site. In order to confirm and extend these observations, in the present study, it was shown that dextran sulfate does not inhibit the binding of OKT4A, OKT4C, Leu3a, or B66.6 to CD4+ cells as measured by cytofluorography. Next, recombinant forms of CD4 (rT4) and gp120 (rgp120) were utilized to directly study their molecular interaction in the absence of other viral or cellular structures. Reciprocal solid phase ELISA assays were developed to study directly the effects of sulfated polysaccharides on the binding of rT4 to immobilized rgp120 and vice versa. Dextran sulfate, heparin, and fucoidan, but not chondroitin sulfate, inhibited the binding of rgp120 to rT4. Importantly, dextran sulfate and heparin pre-treatment of immobilized rT4, but not immobilized rgp120, inhibited rT4-rgp120 binding. Taken together, these data suggest that while both sulfated polysaccharides and anti-CD4 mAb inhibit gp120 binding, the sulfated polysaccharides interact with sites on CD4 that are distinct from those with which the antibodies bind.