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| Name | Class |
|---|---|
| Wellcome Trust | OTHER |
| Médecins Sans Frontières, Belgium | OTHER |
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The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements.
The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen.
There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped.
Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose.
The primary endpoint is virological suppression (viral load <50 copies/mL) at 24 weeks.
A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Supplementary dose | Active Comparator | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. |
|
| Placebo dose | Placebo Comparator | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dolutegravir 50 mg | Drug | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| Measure | Description | Time Frame |
|---|---|---|
| Virological Suppression at 24 Weeks | Proportion of participants with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm | 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Virological Suppression at 24 Weeks (Sensitivity Analysis) | Proportion of participants with HIV viral load <50 copies/mL at 24 weeks using pre-specified sensitivity analyses | 24 weeks |
| Virological Suppression at 12 Weeks (Modified ITT) |
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Inclusion Criteria:
HIV positive patients over 18 years old, who have failed first-line ART regimen of tenofovir-emtricitabine/lamivudine-efavirenz, are able to attend the study clinic for one year of scheduled visits and who have given written, informed consent will be enrolled in this study. In female patients of child-bearing potential, those willing to use effective and reliable contraception for the duration of the study will be eligible.
Failure of a first-line regimen is defined as a viral load (VL) of >1000 copies/mL (within the previous two months) and an immediately prior VL >1000 copies/mL, taken 2-24 months prior (based on data captured by National Health Laboratory Service).
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Graeme Meintjes, PhD | University of Cape Town | Principal Investigator |
| Claire Keene | Médecins Sans Frontières, Belgium | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Khayelitsha Site B/Ubuntu Community Health Clinic | Cape Town | Western Cape | 8001 | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38372621 | Derived | Griesel R, Banda CG, Zhao Y, Omar Z, Wiesner L, Meintjes G, Sinxadi P, Maartens G. Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen. J Acquir Immune Defic Syndr. 2024 May 1;96(1):85-91. doi: 10.1097/QAI.0000000000003402. | |
| 36706364 | Derived |
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Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by Human Research Ethics Committee (HREC) that approved the initial study).
From the time the final results are published
Data will be shared with other organisations or individuals for further research upon a reasonable request to the University of Cape Town PI, provided that certain conditions are met (including but not limited to the ethical standards upheld by HREC that approved the initial study).
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Stage 1 of the ARTIST study was a single-arm prospective cohort study of second-line TLD regimen with supplementary dolutegravir dose (50 mg twice daily) for two weeks in patients failing a NNRTI-based regimen. After completion of stage 1, the study progressed to enrol 130 participants in stage 2.
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| ID | Title | Description |
|---|---|---|
| FG000 | Stage 2: Supplementary Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| FG001 | Stage 2: Placebo Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. Placebo: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| FG002 | Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Stage 2: Supplementary Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Virological Suppression at 24 Weeks | Proportion of participants with HIV viral load <50 copies/mL at 24 weeks analysed by modified intention to treat (ITT) and according to the FDA snapshot algorithm | mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes. | Posted | Count of Participants | Participants | 24 weeks |
|
48 weeks
Adverse events were evaluated and graded at all study visits according to the Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Stage 2: Supplementary Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| severe COVID-19 | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| acute psychosis | Psychiatric disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof Graeme Meintjes | University of Cape Town | +27 (0) 21 4066075 | Graeme.Meintjes@uct.ac.za |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 17, 2020 | Jul 17, 2020 | Prot_005.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 9, 2022 | May 9, 2022 | SAP_007.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 17, 2020 | Jul 17, 2020 | ICF_006.pdf |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| C562325 | dolutegravir |
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This study will be a phase 2, randomised, double-blind, placebo-controlled trial of tenofovir-lamivudine-dolutegravir fixed-dose combination daily with a lead-in supplementary 50 mg dose of dolutegravir versus matching placebo taken 12 hours later for the first 14 days in patients failing a first-line tenofovir-emtricitabine/lamivudine-efavirenz regimen.
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|
|
| Placebo | Drug | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
|
Proportion of participants with HIV viral load <50 copies/mL at 12 weeks analysed by modified ITT.
| 12 weeks |
| Antiretroviral Resistance Mutations by Genotypic Resistance Testing | To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks | 24 weeks |
| CD4 Change at 24 Weeks | Change in CD4 count from screening to week 24 | 24 weeks |
| Adverse Events | To describe grade 3 or 4 adverse events and serious adverse events | 24 weeks |
| All-cause Mortality | To describe all-cause mortality. | 24 weeks |
| Adherence to Treatment | To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks | 24 weeks |
| Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28 | First 28 days |
| Keene CM, Cassidy T, Zhao Y, Griesel R, Jackson A, Sayed K, Omar Z, Hill A, Ngwenya O, Van Zyl G, Flowers T, Goemaere E, Maartens G, Meintjes G. Recycling Tenofovir in Second-line Antiretroviral Treatment With Dolutegravir: Outcomes and Viral Load Trajectories to 72 weeks. J Acquir Immune Defic Syndr. 2023 Apr 15;92(5):422-429. doi: 10.1097/QAI.0000000000003157. |
| 36645792 | Derived | Zhao Y, Griesel R, Omar Z, Simmons B, Hill A, van Zyl G, Keene C, Maartens G, Meintjes G. Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial. Clin Infect Dis. 2023 May 24;76(10):1832-1840. doi: 10.1093/cid/ciad023. |
| 36017341 | Derived | Zhao Y, Keene C, Griesel R, Sayed K, Gcwabe Z, Jackson A, Ngwenya O, Schutz C, Goliath R, Cassidy T, Goemaere E, Hill A, Maartens G, Meintjes G. AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial. Wellcome Open Res. 2021 Feb 17;6:33. doi: 10.12688/wellcomeopenres.16597.1. eCollection 2021. |
| BG001 | Stage 2: Placebo Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. Placebo: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| BG002 | Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Weight | Median | Inter-Quartile Range | kg |
|
| BMI | Median | Inter-Quartile Range | kg/m2 |
|
| CD4 cell count | Median | Inter-Quartile Range | cells/μL |
|
| HIV-1 RNA | Median | Inter-Quartile Range | log10 copies/mL |
|
| Time receiving first-line ART | Median | Inter-Quartile Range | months |
|
| Two fully active NRTIs | Denominators indicate the numbers of participants with available viral sequences. | Count of Participants | Participants |
|
| Resistance to 1 NRTI | Denominators indicate the numbers of participants with available viral sequences | Count of Participants | Participants |
|
| Resistance to both NRTIs | Denominators indicate the numbers of participants with available viral sequences | Count of Participants | Participants |
|
| TFV-DP concentration | Median | Inter-Quartile Range | fmol/punch |
|
| OG001 | Stage 2: Placebo Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. Placebo: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
| OG002 | Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). |
|
|
| Secondary | Virological Suppression at 24 Weeks (Sensitivity Analysis) | Proportion of participants with HIV viral load <50 copies/mL at 24 weeks using pre-specified sensitivity analyses | Sensitivity analysis excludes those excluded from mITT analysis, as well as loss to follow-up, missing viral load within the window, switching study drug for reasons other than treatment failure, and evidence of poor adherence (tenofovir diphosphate <350 fmol/punch). | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | Virological Suppression at 12 Weeks (Modified ITT) | Proportion of participants with HIV viral load <50 copies/mL at 12 weeks analysed by modified ITT. | mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes. | Posted | Count of Participants | Participants | 12 weeks |
|
|
|
| Secondary | Antiretroviral Resistance Mutations by Genotypic Resistance Testing | To describe dolutegravir resistance or emergent resistance mutations to tenofovir or lamivudine in participants eligible for genotypic resistance testing by 24 weeks | If any HIV-1 RNA after week 12 was ≥50 copies/mL, or if there was <1 log10 decline in HIV-1 RNA from baseline, or if HIV-1 RNA was suppressed and sub- sequently rebound to ≥50 copies/mL, enhanced adherence counseling was performed, and HIV-1 RNA measurement was repeated after 2 weeks. If the repeat HIV-1 RNA was ≥500 copies/mL, a genotypic antiretroviral resistance test was performed. | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | CD4 Change at 24 Weeks | Change in CD4 count from screening to week 24 | Posted | Median | Inter-Quartile Range | cells/μL | 24 weeks |
|
|
|
| Secondary | Adverse Events | To describe grade 3 or 4 adverse events and serious adverse events | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | All-cause Mortality | To describe all-cause mortality. | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
| Secondary | Adherence to Treatment | To describe tenofovir-diphosphate (TFV-DP) concentrations (ng/mL) at 24 weeks | We monitored adherence with tenofovir diphosphate (TFV-DP) concentrations using stored dried blood spot specimens. | Posted | Median | Inter-Quartile Range | fmol/punch | 24 weeks |
|
|
|
| Secondary | Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28 | To evaluate the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28 | Posted | Geometric Mean | 90% Confidence Interval | ratio | First 28 days |
|
|
|
| 1 |
| 65 |
| 2 |
| 65 |
| 2 |
| 65 |
| EG001 | Stage 2: Placebo Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days. Placebo: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). | 0 | 65 | 0 | 65 | 5 | 65 |
| EG002 | Stage 1: TLD Regimen With Supplementary Dolutegravir Dose | Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. Dolutegravir 50 mg: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). | 0 | 62 | 9 | 62 | 3 | 62 |
| acute psychosis | Psychiatric disorders | Systematic Assessment |
|
| fractured tibia | Injury, poisoning and procedural complications | Systematic Assessment |
|
| thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| urinary tract infection | Renal and urinary disorders | Systematic Assessment |
|
| incident pulmonary tuberculosis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| stab chest | Injury, poisoning and procedural complications | Systematic Assessment |
|
| acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| gastritis | Gastrointestinal disorders | Systematic Assessment |
|
| perianal abscess | Gastrointestinal disorders | Systematic Assessment |
|
| condylomata acuminata | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| incident pulmonary tuberculosis | Infections and infestations | Systematic Assessment |
|
| raised random glucose | Endocrine disorders | Systematic Assessment |
|
| acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| headache | Nervous system disorders | Systematic Assessment |
|
| neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| raised blood pressure | Cardiac disorders | Systematic Assessment |
|
Not provided
Not provided
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| Male |
|